Aminocyclohexyl ether compounds and uses thereof

ABSTRACT

Aminocyclohexyl ether compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses uses for the compounds and compositions, including the treatment of arrhythmia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/690,361 filed Mar. 23, 2007 (U.S. Pat. No. 7,767,830); which is acontinuation of U.S. patent application Ser. No. 10/555,364 filed Oct.16, 2006 (now abandoned), which is a U.S. National Phase Application ofPCT/US2003/034655 filed Oct. 31, 2003, which claims priority to U.S.Provisional Patent Application No. 60/467,159 filed May 2, 2003, U.S.Provisional Patent Application No. 60/476,083 filed Jun. 4, 2003, U.S.Provisional Patent Application No. 60/475,884 filed Jun. 5, 2003, U.S.Provisional Patent Application No. 60/475,912 filed Jun. 5, 2003, U.S.Provisional Patent Application No. 60/476,447 filed Jun. 5, 2003, U.S.Provisional Patent Application No. 60/489,659 filed Jul. 23, 2003, andU.S. Provisional Patent Application No. 60/493,392 filed Aug. 7, 2003.All of these applications are incorporated herein by reference in theirentireties.

BACKGROUND

1. Technical Field

The present invention is directed to aminocyclohexyl ether compounds,pharmaceutical compositions, and processes for the synthesis of theaminocyclohexyl ether compounds, and therapeutic uses thereof.

2. Description of the Related Art

Ion channels are ubiquitous membrane proteins in the cells ofwarm-blooded animals such as mammals. Their critical physiological rolesinclude control of the electrical potential across the membrane,mediation of ionic and fluid balance, facilitation of neuromuscular andneuronal transmission, rapid transmembrane signal transduction, andregulation of secretion and contractility.

For example, cardiac ion channels are proteins that reside in the cellmembrane and control the electrical activity of cardiac tissue. Inresponse to external stimuli, such as changes in potential across thecell membrane, these ion channels can form a pore through the cellmembrane, and allow movement of specific ions into or out of the cell.The integrated behavior of thousands of ion channels in a single cellresults in an ionic current, and the integrated behavior of many ofthese ionic currents makes up the characteristic cardiac actionpotential.

Arrhythmia is a variation from the normal rhythm of the heart beat andgenerally represents the end product of abnormal ion-channel structure,number or function. Both atrial arrhythmias and ventricular arrhythmiasare known. The major cause of fatalities due to cardiac arrhythmias isthe subtype of ventricular arrhythmias known as ventricular fibrillation(VF). Conservative estimates indicate that, in the U.S. alone, each yearover one million Americans will have a new or recurrent coronary attack(defined as myocardial infarction or fatal coronary heart disease).About 650,000 of these will be first heart attacks and 450,000 will berecurrent attacks. About one-third of the people experiencing theseattacks will die of them. At least 250,000 people a year die of coronaryheart disease within 1 hour of the onset of symptoms and before theyreach a hospital. These are sudden deaths caused by cardiac arrest,usually resulting from ventricular fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinicalpractice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2;Kannel and Wolf, Am. Heart J. 123(1):264-7 Jan. 1992). Its prevalence islikely to increase as the population ages and it is estimated that 3-5%of patients over the age of 60 years have AF (Kannel W. B., Abbot R. D.,Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018-22, 1982;Wolf P. A., Abbot R. D., Kannel W. B. Stroke. 22(8):983-8, 1991). WhileAF is rarely fatal, it can impair cardiac function and is a major causeof stroke (Hinton R. C., Kistler J. P., Fallon J. T., Friedlich A. L.,Fisher C. M., American Journal of Cardiology 40(4):509-13, 1977; Wolf P.A., Abbot R. D., Kannel W. B., Archives of Internal Medicine147(9):1561-4, 1987; Wolf P. A., Abbot R. D., Kannel W. B. Stroke.22(8):983-8, 1991; Cabin H. S., Clubb K. S., Hall C., Perlmutter R. A.,Feinstein A. R., American Journal of Cardiology 65(16):1112-6, 1990).

WO95/08544 discloses a class of aminocyclohexylester compounds as usefulin the treatment of arrhythmias.

WO93/19056 discloses a class of aminocyclohexylamides as useful in thetreatment of arrhythmia and in the inducement of local anaesthesia.

WO99/50225 discloses a class of aminocyclohexylether compounds as usefulin the treatment of arrhythmias.

Antiarrhythmic agents have been developed to prevent or alleviatecardiac arrhythmia. For example, Class I antiarrhythmic compounds havebeen used to treat supraventricular arrhythmias and ventriculararrhythmias. Treatment of ventricular arrhythmia is very important sincesuch an arrhythmia can be fatal. Serious ventricular arrhythmias(ventricular tachycardia and ventricular fibrillation) occur most oftenin the presence of myocardial ischemia and/or infarction. Ventricularfibrillation often occurs in the setting of acute myocardial ischemia,before infarction fully develops. At present, there is no satisfactorypharmacotherapy for the treatment and/or prevention of ventricularfibrillation during acute ischemia. In fact, many Class I antiarrhythmiccompounds may actually increase mortality in patients who have had amyocardial infarction.

Class Ia, Ic and III antiarrhythmic drugs have been used to convertrecent onset AF to sinus rhythm and prevent recurrence of the arrhythmia(Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs48(3):345-71, 1994). However, drug therapy is often limited by adverseeffects, including the possibility of increased mortality, andinadequate efficacy (Feld G. K., Circulation. 83(6):2248-50, 1990;Coplen S. E., Antman E. M., Berlin J. A., Hewitt P., Chalmers T. C.,Circulation 1991; 83(2):714 and Circulation 82(4):1106-16, 1990; FlakerG. C., Blackshear J. L., McBride R., Kronmal R. A., Halperin J. L., HartR. G., Journal of the American College of Cardiology 20(3):527-32, 1992;CAST, N. Engl. J. Med. 321:406, 1989; Nattel S., CardiovascularResearch. 37(3):567-77, 1998). Conversion rates for Class Iantiarrhythmics range between 50-90% (Nattel S., Hadjis T., Talajic M.,Drugs 48(3):345-71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal ofCardiovascular Electrophysiology. 9(8 Suppl):S104-8, 1998). Class IIIantiarrhythmics appear to be more effective for terminating atrialflutter than for AF and are generally regarded as less effective thanClass I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M.,Drugs. 48(3):345-71, 1994; Capucci A., Aschieri D., Villani G. Q., Drugs& Aging 13(1):51-70, 1998). Examples of such drugs include ibutilide,dofetilide and sotalol. Conversion rates for these drugs range between30-50% for recent onset AF (Capucci A., Aschieri D., Villani G. Q.,Drugs & Aging 13(1):51-70, 1998), and they are also associated with arisk of the induction of Torsades de Pointes ventriculartachyarrhythmias. For ibutilide, the risk of ventricular proarrhythmiais estimated at ˜4.4%, with ˜1.7% of patients requiring cardioversionfor refractory ventricular arrhythmias (Kowey P. R., VanderLugt J. T.,Luderer J. R., American Journal of Cardiology 78(8A):46-52, 1996). Suchevents are particularly tragic in the case of AF as this arrhythmia israrely a fatal in and of itself.

There remains a need in the art to identify new antiarrhythmictreatments, for both ventricular arrhythmias as well as for atrialarrhythmias. The present invention fulfills this need, and furtherprovides other related advantages.

BRIEF SUMMARY

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, with the proviso thatR₃, R₄ and R₅ cannot all be hydrogen.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, with the proviso thatR₃, R₄ and R₅ cannot all be hydrogen.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, with the proviso thatR₃, R₄ and R₅ cannot all be hydrogen.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, with the proviso thatR₃, R₄ and R₅ cannot all be hydrogen.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, with the proviso thatR₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound or anysalt thereof, or any solvate thereof, or mixture comprising one or moresaid compounds or any salt thereof, or any solvate thereof, selectedfrom the group consisting of:

Structure Chemical name

(1R,2R)/(1S,2S)-2-[(3R)/(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)/(1S,2S)-2-[(3R)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)/(1S,2S)-2-[(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2S)/(1S,2R)-2-[(3R)/(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

In another embodiment, the present invention provides a composition thatincludes one or more of the compounds listed in the above table, orincludes a solvate or a pharmaceutically acceptable salt of one or moreof the compounds listed in the above table. The composition may or maynot include additional components as is described elsewhere in detail inthis patent.

In one embodiment, the present invention provides a compound, or mixturecomprising compounds, or any solvate thereof, selected from the groupconsisting of:

Cpd. # Structure Chemical name 1

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 2

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 3

(1R,2R)/(1S,2S)-2-[(3R)/(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 4

(1R,2R)/(1S,2S)-2-[(3R)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 5

(1R,2R)/(1S,2S)-2-[(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 6

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 7

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride

In another embodiment, the present invention provides a composition thatincludes one or more of the compounds listed in the above table, orincludes a solvate of one or more of the compounds listed in the abovetable. The composition may or may not include additional components asis described elsewhere in detail in this patent.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is.(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

The present invention also provides protenated versions of all of thecompounds described in this patent. That is, for each compound describedin this patent, the invention also includes the quaternary protenatedamine form of the compound. These quaternary protenated amine forms ofthe compounds may be present in the solid phase, for example incrystalline or amorphous form, and may be present in solution. Thesequaternary protenated amine forms of the compounds may be associatedwith pharmaceutically acceptable anionic counter ions, including but notlimited to those described in for example: “Handbook of PharmaceuticalSalts, Properties, Selection, and Use”, P. Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG),2002.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from any of thecompounds described in this patent or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof, in combination with a pharmaceutically acceptable carrier,diluent or excipient, and further provides a method for the manufactureof such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof, in combination with a pharmaceutically acceptable carrier,diluent or excipient, and further provides a method for the manufactureof such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, or metabolite thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof, in combination with a pharmaceutically acceptable carrier,diluent or excipient, and further provides a method for the manufactureof such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination with apharmaceutically acceptable carrier, diluent or excipient, and furtherprovides a method for the manufacture of such a composition ormedicament.

In other embodiments, the present invention provides one or morecompounds of the present invention such as those according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof; or a composition or medicament that includes said compound ormixture comprising compounds as described above, for use in methods formodulating ion channel activity in a warm-blooded animal or formodulating ion channel activity in vitro. In one version of thisembodiment, the warm-blooded animal in which the ion channel activity ismodulated is a mammal; in one version, the warm-blooded animal is ahuman; in one version, the warm-blooded animal is a farm animal.

As disclosed within the present invention, a variety of cardiacpathological conditions may be treated and/or prevented by the use ofone or more compounds of the present invention such as those accordingto formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove. Without being bound by theory, the inventors believe that thecompounds of the present invention are ion channel modulating compoundsthat either singly or together with one or more additional compounds areable to selectively modulate certain ionic currents. The ion currentsreferred to herein are generally cardiac currents and more specifically,are the sodium currents and early repolarising currents.

Throughout this patent the inventors describe various means by whichthey believe the compounds described in this patent may act. Suchdescriptions are not intended to be limiting but represent theinventors' belief as to how the compounds may act.

The pathological conditions that may be treated and/or prevented by thepresent invention may include, but are not limited to, variouscardiovascular diseases.

The cardiac pathological conditions that may be treated and/or preventedby the present invention may include, but are not limited to,arrhythmias such as the various types of atrial and ventriculararrhythmias, e.g., atrial fibrillation, atrial flutter, ventricularfibrillation, ventricular flutter.

In another embodiment, the present invention provides ion channelmodulating compounds that can be used to selectively inhibit cardiacearly repolarising currents and cardiac sodium currents under conditionswhere an “arrhythmogenic substrate” is present in the heart. An“arrhythmogenic substrate” is characterized by a reduction in cardiacaction potential duration and/or changes in action potential morphology,premature action potentials, high heart rates and may also includeincreased variability in the time between action potentials and anincrease in cardiac milieu acidity due to ischaemia or inflammation.Changes such as these are observed during conditions of myocardialischaemia or inflammation and those conditions that precede the onset ofarrhythmias such as atrial fibrillation.

In other embodiments, the present invention provides a method formodulating ion channel activity in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof, an effectiveamount of one or more compounds of the present invention such as thoseaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove.

In other embodiments, the present invention provides a method formodulating ion channel activity in an in vitro setting comprisingadministering in vitro an effective amount of one or more compounds ofthe present invention such as those according to formula (IA), (IB),(IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt,ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, metabolite, metabolicprecursor or prodrug thereof, including isolated enantiomeric,diastereomeric and geometric isomers thereof, and mixtures thereof; or acomposition or medicament that includes said compound or mixturecomprising compounds as described above.

In other embodiments, the present invention provides a method forblocking/inhibiting the activity/conductance of ion channel in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof, an effective amount of one or more compounds of thepresent invention such as those according to formula (IA), (IB), (IC),(ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method formodulating potassium ion channel activity in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method formodulating cardiac sodium currents activity in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method formodulating cardiac early repolarising currents and cardiac sodiumcurrents ion channel activity in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof, an effectiveamount of one or more compounds of the present invention such as thoseaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove.

In other embodiments, the present invention provides a method fortreating and/or preventing arrhythmia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In another embodiments, the present invention provides a method fortreating and/or preventing arrhythmia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In other embodiments, the present invention provides a composition ormedicament that contain one or more compounds of the present inventionsuch as those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof as described above, inan amount effective to treat a disease or condition in a warm-bloodedanimal suffering from or having the disease or condition, and/or preventa disease or condition in a warm-blooded animal that would otherwiseoccur, and further contains a pharmaceutically acceptable carrier,diluent or excipient.

The invention further provides for methods of treating a disease orcondition in a warm-blooded animal suffering from or having the diseaseor condition, and/or preventing a disease or condition from arising in awarm-blooded animal, wherein a therapeutically effective amount of oneor more compounds of the present invention such as those according toformula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof; or a composition or medicament that includes said compound ormixture comprising compounds as described above, is administered to awarm-blooded animal in need thereof. By way of illustration and not byway of limitation, examples of some of the diseases, disorders andconditions to which the compounds, compositions, medicaments and methodsof the present invention have applicability are as follows: arrhythmia,atrial arrhythmia, ventricular arrhythmia, atrial fibrillation,ventricular fibrillation, atrial flutter, ventricular flutter, diseasesof the central nervous system, convulsion, epileptic spasms, depression,anxiety, schizophrenia, Parkinson's disease, respiratory disorders,cystic fibrosis, asthma, cough, inflammation, arthritis, allergies,gastrointestinal disorders, urinary incontinence, irritable bowelsyndrome, cardiovascular diseases, cerebral or myocardial ischemias,hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases,diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis,paramyotonia congentia, malignant hyperthermia, hyperkalemic periodicparalysis, Thomsen's myotonia, autoimmune disorders, graft rejection inorgan transplantation or bone marrow transplantation, heart failure,hypotension, Alzheimer's disease or other mental disorder, and alopecia.

In one version, the compounds of the present invention may be used totreat and/or prevent arrhythmia, atrial arrhythmia, ventriculararrhythmia, atrial fibrillation, ventricular fibrillation, atrialflutter, or ventricular flutter; in another version the compounds may beused to treat arrhythmia, atrial arrhythmia, ventricular arrhythmia,atrial fibrillation, ventricular fibrillation, atrial flutter, orventricular flutter; in another version the compounds may be used toprevent arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrialfibrillation, ventricular fibrillation, atrial flutter, or ventricularflutter.

In other embodiments, the present invention provides a composition ormedicament containing an amount of one or more compounds of the presentinvention such as those according to formula (IA), (IB), (IC), (ID), or(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof as described above,effective to produce analgesia or local anesthesia in a warm-bloodedanimal in need thereof, and a pharmaceutically acceptable carrier,diluent, or excipient.

The invention further provides a method for producing, analgesia orlocal anesthesia in a warm-blooded animal which includes administeringto a warm-blooded animal in need thereof an effective amount of one ormore compounds of the present invention such as those according toformula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof, or a composition or medicament that includes said compound ormixture comprising compounds as described above. These compositions,medicaments and methods may be used to relieve or forestall thesensation of pain in a warm-blooded animal.

In other embodiments, the present invention provides a composition ormedicament containing an amount of one or more compounds of the presentinvention such as those according to formula (IA), (IB), (IC), (ID), or(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof as described above,effective to enhance the libido in a warm-blooded animal in needthereof, and a pharmaceutically acceptable carrier, diluent, orexcipient.

The invention further provides a method for enhancing libido in awarm-blooded animal which includes administering to a warm-bloodedanimal in need thereof an effective amount of one or more compounds ofthe present invention such as those according to formula (IA), (IB),(IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt,ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, metabolite, metabolicprecursor or prodrug thereof, including isolated enantiomeric,diastereomeric and geometric isomers thereof, and mixtures thereof, or acomposition or medicament that includes said compound or mixturecomprising compounds as described above. These compositions and methodsmay be used, for example, to treat a sexual dysfunction, e.g., impotencein males, and/or to enhance the sexual desire of a patient without asexual dysfunction. As another example, the therapeutically effectiveamount may be administered to a bull (or other breeding stock), topromote increased semen ejaculation, where the ejaculated semen iscollected and stored for use as it is needed to impregnate female cowsin promotion of a breeding program.

The compounds of the present invention are effective antiarrhythmicagents. The compounds according to the present invention have been foundto exhibit advantageously low Central Nervous System (CNS) toxicitywhilst retaining high antiarrhythmic activity.

In another embodiment the present invention provides methods for thesynthesis of compounds of the present invention such as those accordingto formula (IA), (IB), (IC), (ID), or (IE), and in particular methodsfor the synthesis of the compounds;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride;

Some general synthetic processes for aminocyclohexyl ethers have beendescribed in WO 99/50225 and references cited therein.

These and other embodiments of the present invention will become evidentupon reference to the following description, drawings and examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a reaction sequence whereby the followingaminocyclohexyl ether compounds of the present invention may besynthesized:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 1);

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 2);

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 3);

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 4);

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1R,2R)/(1S,2S)-2-[(3s)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 5);

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 6);

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 7);

FIG. 2 illustrates a synthetic methodology that may be employed toprepare a trans-aminocyclohexyl ether compound of the present invention.

FIG. 3 illustrates a synthetic methodology for preparing amine 1erequired for the formation of amino alcohol 2e (as shown in FIG. 2).

FIG. 4 illustrates a synthetic sequence that may be used to prepare acis-aminocyclohexyl ether compound of the present invention such ascompound 25.

FIG. 5 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 6 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 7 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 8 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 9 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 10 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 11 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 12 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 13 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 14 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 15 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 16 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 17 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 18 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 19 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 20 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 21 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 22 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 23 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 24 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 25 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 26 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 27 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 28 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 29 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 30 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 31 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 32 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 33 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 34 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 35 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 36 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 37 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(55).

FIG. 38 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(64).

FIG. 39 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(67).

FIG. 40 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(71).

FIG. 41 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(53).

FIG. 42 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(62).

FIG. 43 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(52).

FIG. 44 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(61).

FIG. 45 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 46 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 47 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 48 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 49 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 50 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 51 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 52 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 53 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 54 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 55 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 56 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 57 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 58 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 59 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 60 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 61 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 62 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 63 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 64 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 65 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 66 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 67 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 68 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 69 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 70 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 71 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 72 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 73 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 74 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 75 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 76 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 77 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(74).

FIG. 78 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(78).

FIG. 79 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(80).

FIG. 80 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(82).

FIG. 81 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(73).

FIG. 82 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(77).

FIG. 83 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(72).

FIG. 84 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(76).

FIG. 85 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 86 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 87 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 88 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 89 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 90 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 91 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 92 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 93 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 94 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 95 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially pure compoundof formula (55).

FIG. 96 illustrates general a reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially pure compoundof formula (55).

FIG. 97 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(64).

FIG. 98 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(64).

FIG. 99 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(64).

FIG. 100 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially pure compoundof formula (85) and a stereoisomerically substantially pure compound offormula (86).

FIG. 101 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(62) and a stereoisomerically substantially pure compound of formula(89).

FIG. 102 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(87) and a stereoisomerically substantially pure compound of formula(90).

FIG. 103 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(62) and a stereoisomerically substantially pure compound of formula(87).

FIG. 104 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 105 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 106 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 107 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 108 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 109 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 110 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 111 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 112 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 113 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 114 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 115 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 116 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially pure compoundof formula (74).

FIG. 117 illustrates general a reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially pure compoundof formula (74).

FIG. 118 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(78).

FIG. 119 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(78).

FIG. 120 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(78).

FIG. 121 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 122 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 123 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (69).

FIG. 124 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 125 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 126 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (69).

FIG. 127 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 128 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 129 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (69).

FIG. 130 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 131 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 132 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (69).

FIG. 133 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 134 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 135 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (69).

FIG. 136 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 137 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (66).

FIG. 138 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1R,2R)-aminocyclohexylether compound of formula (69).

FIG. 139 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(55).

FIG. 140 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(64).

FIG. 141 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(94).

FIG. 142 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(98).

FIG. 143 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(93).

FIG. 144 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(97).

FIG. 145 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(92).

FIG. 146 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(96).

FIG. 147 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 148 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 149 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (81).

FIG. 150 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 151 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 152 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (81).

FIG. 153 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 154 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 155 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (81).

FIG. 156 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 157 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 158 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (81).

FIG. 159 illustrates a general reaction scheme that may be used as aprocess for preparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 160 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 161 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially puretrans-(1S,2S)-aminocyclohexylether compound of formula (81).

FIG. 162 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(74).

FIG. 163 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(78).

FIG. 164 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(84).

FIG. 165 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(62).

FIG. 166 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(99).

FIG. 167 illustrates a reaction scheme that may be used as a process forpreparing a stereoisomerically substantially pure compound of formula(100).

DETAILED DESCRIPTION

As noted above, the present invention is directed to aminocyclohexylether compounds of formula such as (IA), (IB), (IC), (ID), or (IE),methods of manufacture thereof, pharmaceutical compositions containingthe aminocyclohexyl ether compounds, and various uses for the compoundsand compositions. Such uses include the treatment of arrhythmias, ionchannel modulation and other uses as described herein.

An understanding of the present invention may be aided by reference tothe following definitions and explanation of conventions used herein:

The aminocyclohexyl ether compounds of the invention have an etheroxygen atom at position 1 of a cyclohexane ring, and an amine nitrogenatom at position 2 of the cyclohexane ring, with other positionsnumbered in corresponding order as shown below in structure (A):

The bonds from the cyclohexane ring to the 1-oxygen and 2-nitrogen atomsin the above formula may be relatively disposed in either a cis or transrelationship. In a preferred embodiment of the present invention, thestereochemistry of the amine and ether substituents of the cyclohexanering is either (R,R)-trans or (S,S)-trans. In another preferredembodiment the stereochemistry is either (R,S)-cis or (S,R)-cis.

A wavy bond from a substituent to the central cyclohexane ring indicatesthat that group may be located on either side of the plane of thecentral ring. When a wavy bond is shown intersecting a ring, thisindicates that the indicated substituent group may be attached to anyposition on the ring capable of bonding to the substituent group andthat the substituent group may lie above or below the plane of the ringsystem to which it is bound.

Following the standard chemical literature description practice and asused in this patent, a full wedge bond means above the ring plane, and adashed wedge bond means below the ring plane; one full bond and onedashed bond (i.e., -----) means a trans configuration, whereas two fullbonds or two dashed bonds means a cis configuration.

In the formulae depicted herein, a bond to a substituent and/or a bondthat links a molecular fragment to the remainder of a compound may beshown as intersecting one or more bonds in a ring structure. Thisindicates that the bond may be attached to any one of the atoms thatconstitutes the ring structure, so long as a hydrogen atom couldotherwise be present at that atom. Where no particular substituent(s) isidentified for a particular position in a structure, then hydrogen(s) ispresent at that position. For example, compounds of the inventioncontaining compounds having the group (B):

where the group (B) is intended to encompass groups wherein any ringatom that could otherwise be substituted with hydrogen, may instead besubstituted with either R₃, R₄ or R₅, with the proviso that each of R₃,R₄ and R₅ appears once and only once on the ring. Ring atoms that arenot substituted with any of R₃, R₄ or R₅ are substituted with hydrogen.In those instances where the invention specifies that a non-aromaticring is substituted with one or more functional groups, and thosefunctional groups are shown connected to the non-aromatic ring withbonds that bisect ring bonds, then the functional groups may be presentat different atoms of the ring, or on the same atom of the ring, so longas that atom could otherwise be substituted with a hydrogen atom.

The compounds of the present invention contain at least two asymmetriccarbon atoms and thus exist as enantiomers and diastereomers. Unlessotherwise indicated, the present invention includes all enantiomeric anddiastereomeric forms of the aminocyclohexyl ether compounds of theinvention. Pure stereoisomers, mixtures of enantiomers and/ordiastereomers, and mixtures of different compounds of the invention areincluded within the present invention. Thus, compounds of the presentinvention may occur as racemates, racemic mixtures and as individualdiastereomers, or enantiomers, unless a specific stereoisomer enantiomeror diastereomer is identified, with all isomeric forms being included inthe present invention. A racemate or racemic mixture does not imply a50:50 mixture of stereoisomers. Unless otherwise noted, the phrase“stereoisomerically substantially pure” generally refers to thoseasymmetric carbon atoms that are described or illustrated in thestructural formulae for that compound.

As an example, and in no way limiting the generality of the above, acompound designated with the formula

includes at least three chiral centers (the cyclohexyl carbon bonded tothe oxygen, the cyclohexyl carbon bonded to the nitrogen, and thepyrrolidinyl carbon bonded to the oxygen) and therefore has at leasteight separate stereoisomers, which are(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(R₃, R₄ and R₅ substitutedphenethoxy)-cyclohexane; (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(R₃, R₄and R₅ substituted phenethoxy)-cyclohexane;(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(R₃, R₄ and R₅ substitutedphenethoxy)-cyclohexane; (1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(R₃, R₄and R₅ substituted phenethoxy)-cyclohexane;(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(R₃, R₄ and R₅ substitutedphenethoxy)-cyclohexane; (1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(R₃, R₄and R₅ substituted phenethoxy)-cyclohexane;(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(R₃, R₄ and R₅ substitutedphenethoxy)-cyclohexane; and (1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(R₃,R₄ and R₅ substituted phenethoxy)-cyclohexane; and, unless the contextmakes plain otherwise, as used in this patent a compound of the formula

means a composition that includes a component that is either one of theeight pure enantiomeric forms of the indicated compound or is a mixtureof any two or more of the pure enantiomeric forms, where the mixture caninclude any number of the enantiomeric forms in any ratio.

As an example, and in no way limiting the generality of the above,unless the context make plain otherwise as used in this patent acompound designated with the chemical formula(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemeans a composition that includes a component that is either one of thetwo pure enantiomeric forms of the indicated compound (i.e.,(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexaneor(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane)or is a racemic mixture of the two pure enantiomeric forms, where theracemic mixture can include any relative amount of the two enantiomers.

The phrase “independently at each occurrence” is intended to mean (i)when any variable occurs more than one time in a compound of theinvention, the definition of that variable at each occurrence isindependent of its definition at every other occurrence; and (ii) theidentity of any one of two different variables (e.g., R₁ within the setR₁ and R₂) is selected without regard the identity of the other memberof the set. However, combinations of substituents and/or variables arepermissible only if such combinations result in compounds that do notviolate the standard rules of chemical valency.

In accordance with the present invention and as used herein, thefollowing terms are defined to have following meanings, unlessexplicitly stated otherwise:

“Acid addition salts” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike, and include but not limited to those described in for example:“Handbook of Pharmaceutical Salts, Properties, Selection, and Use”, P.Heinrich Stahl and Camille G. Wermuth (Eds.), Published by VHCA(Switzerland) and Wiley-VCH (FRG), 2002.

“Alkoxy” refers to an oxygen (O)-atom substituted by an alkyl group, forexample, alkoxy can include but is not limited to methoxy, which mayalso be denoted as —OCH₃, —OMe or a C₁alkoxy.

“Modulating” in connection with the activity of an ion channel meansthat the activity of the ion channel may be either increased ordecreased in response to administration of a compound or composition ormethod of the present invention. Thus, the ion channel may be activated,so as to transport more ions, or may be blocked (inhibited), so thatfewer or no ions are transported by the channel.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985). For example, sterile saline and phosphate-buffered salineat physiological pH may be used. Preservatives, stabilizers, dyes andeven flavoring agents may be provided in the pharmaceutical composition.For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid may be added as preservatives. Id at 1449. In addition,antioxidants and suspending agents may be used. Id.

“Pharmaceutically acceptable salt” refers to salts of the compounds ofthe present invention derived from the combination of such compounds andan organic or inorganic acid (acid addition salts) or an organic orinorganic base (base addition salts). Examples of pharmaceuticallyacceptable salt include but not limited to those described in forexample: “Handbook of Pharmaceutical Salts, Properties, Selection, andUse”, P. Heinrich Stahl and Camille G. Wermuth (Eds.), Published by VHCA(Switzerland) and Wiley-VCH (FRG), 2002. The compounds of the presentinvention may be used in either the free base or salt forms, with bothforms being considered as being within the scope of the presentinvention.

The “therapeutically effective amount” of a compound of the presentinvention will depend on the route of administration, the type ofwarm-blooded animal being treated, and the physical characteristics ofthe specific warm-blooded animal under consideration. These factors andtheir relationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which those skilled in the medical arts will recognize.

Compositions described herein as “containing a compound of for exampleformula (IA)” encompass compositions that contain more than one compoundof formula (IA).

Compounds of the Present Invention

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, with the proviso thatR₃, R₄ and R₅ cannot all be hydrogen.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt thereof, wherein,R₄ and R₅ are independently selected from hydroxy and C₁-C₆alkoxy,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from hydroxy and C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are independently selected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are C₁alkoxy.

In one embodiment, the present invention provides a compound of formula(IA), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are C₁alkoxy.

In another embodiment, the present invention provides a compound offormula (IB), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt thereof, wherein,R₄ and R₅ are independently selected from hydroxy and C₁-C₆alkoxy,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from hydroxy and C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are independently selected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer; crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are C₁alkoxy.

In one embodiment, the present invention provides a compound of formula(IB), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are C₁alkoxy.

In another embodiment, the present invention provides a compound offormula (IC), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt thereof, wherein,R₄ and R₅ are independently selected from hydroxy and C₁-C₆alkoxy,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from hydroxy and C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are independently selected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are C₁alkoxy.

In one embodiment, the present invention provides a compound of formula(IC), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are C₁alkoxy.

In another embodiment, the present invention provides a compound offormula (ID), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyand C₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt thereof, wherein,R₄ and R₅ are independently selected from hydroxy and C₁-C₆alkoxy,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from hydroxy and C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are independently selected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are independentlyselected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₃ ishydrogen, R₄ and R₅ are C₁alkoxy.

In one embodiment, the present invention provides a compound of formula(ID), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₃ is hydrogen, R₄ and R₅ are C₁ alkoxy.

In another embodiment, the present invention provides a compound offormula (IE), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof:

wherein, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof.

In one embodiment; the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt thereof, wherein,R₄ and R₅ are independently selected from hydroxy and C₁-C₆alkoxy,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₄ and R₅ are independently selected fromhydroxy and C₁-C₃alkoxy.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₄ and R₅ areindependently selected from C₁-C₆alkoxy.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₄ and R₅ are independently selected fromC₁-C₃alkoxy.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, wherein, R₄ and R₅ areC₁alkoxy.

In one embodiment, the present invention provides a compound of formula(IE), or a solvate, pharmaceutically acceptable salt thereof, includingisolated enantiomeric, diastereomeric and geometric isomers thereof, andmixtures thereof, wherein, R₄ and R₅ are C₁alkoxy.

In another embodiment, the present invention provides a compound or anysalt thereof, or any solvate thereof, or mixture comprising one or moresaid compounds or any salt thereof, or any solvate thereof, selectedfrom the group consisting of:

Structure Chemical name

(1R,2R)/(1S,2S)-2-[(3R)/(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)/(1S,2S)-2-[(3R)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)/(1S,2S)-2-[(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

(1R,2S)/(1S,2R)-2-[(3R)/(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane

In another embodiment, the present invention provides a composition thatincludes one or more of the compounds listed in the above table, orincludes a solvate or a pharmaceutically acceptable salt of one or moreof the compounds listed in the above table. The composition may or maynot include additional components as is described elsewhere in detail inthis patent.

In another embodiment, the present invention provides a compound, ormixture comprising compounds, or any solvate thereof, selected from thegroup consisting of:

Cpd. # Structure Chemical name 1

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 2

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 3

(1R,2R)/(1S,2S)-2-[(3R)/(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 4

(1R,2R)/(1S,2S)-2-[(3R)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 5

(1R,2R)/(1S,2S)-2-[(3S)- Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 6

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride 7

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]- 1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride

In another embodiment, the present invention provides a composition thatincludes one or more of the compounds listed in the above table, orincludes a solvate of one or more of the compounds listed in the abovetable. The composition may or may not include additional components asis described elsewhere in detail in this patent.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof.

The present invention also provides protenated versions of all of thecompounds described in this patent. That is, for each compound describedin this patent, the invention also includes the quaternary protenatedamine form of the compound. These quaternary protenated amine forms ofthe compounds may be present in the solid phase, for example incrystalline or amorphous form, and may be present in solution. Thesequaternary protenated amine forms of the compounds may be associatedwith pharmaceutically acceptable anionic counter ions, including but notlimited to those described in for example: “Handbook of PharmaceuticalSalts, Properties, Selection, and Use”, P. Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG),2002.

Outline of Method of Preparation of Compounds of the Invention

The aminocyclohexyl ether compounds of the present invention containamino and ether functional groups disposed in a 1,2 arrangement on acyclohexane ring. Accordingly, the amino and ether functional groups maybe disposed in either a cis or trans relationship, relative to oneanother and the plane of the cyclohexane ring as shown on the page in atwo dimensional representation.

The present invention provides synthetic methodology for the preparationof the aminocyclohexyl ether compounds according to the presentinvention as described herein. The aminocyclohexyl ether compoundsdescribed herein may be prepared from aminoalcohols and alcohols byfollowing the general methods described below, and as illustrated in theexamples. Some general synthetic processes for aminocyclohexyl ethershave been described in WO 99/50225 and references cited therein. Otherprocesses that may be used for preparing compounds of the presentinvention are described in the following US provisional patentapplications: U.S. 60/476,083, U.S. 60/476,447, U.S. 60/475,884, U.S.60/475,912 and U.S. 60/489,659, and references cited therein.

Trans compounds of the present invention may be prepared in analogy withknown synthetic methodology. In one method, illustrated in FIG. 1,compounds are prepared by a Williamson ether synthesis (Feuer, H.; Hooz,J. Methods of Formation of the Ether Linkage. In Patai, Wiley: New York,1967; pp 445-492) between an activated form of aminoalcohol 4R with thealkoxide of 3,4-dimethoxyphenethyl alcohol in a polar solvent such asdimethoxyethane (ethylene glycol dimethyl ether) (DME) (FIG. 1) thatprovided the corresponding aminoether 5R in high yield. Subsequentresolution of the diastereomers such as by chromatographic separation(e.g., HPLC) to afford 5RRR and 5SSR followed by hydrogenolysis providedcompound 1 and compound 2 respectively.

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanefree base and the corresponding monohydrochloride (compound 6) and(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanefree base and the corresponding monohydrochloride (compound 7) areobtained using a similar synthetic sequence but starting with3-(S)-hydroxypyrrolidine.

Hydrogenolysis of(1R,2R)/(1S,2S)-2-[(3R)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane(5R) provided(1R,2R)/(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanefree base and the corresponding monohydrochloride (compound 4).Similarly, starting with 3-(S)-hydroxypyrrolidine instead of3-(R)-hydroxypyrrolidine and following the same synthetic sequence willafford(1R,2R)/(1S,2S)-2-[(3S)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane.The latter on hydrogenolysis will provide(1R,2R)/(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanefree base and the corresponding monohydrochloride (compound 5).(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base and the corresponding monohydrochloride (compound 3) can alsobe synthesized by similar process by starting with racemic3-hydroxypyrrolidine.

FIG. 2 shows a second general methodology by which compounds of thepresent invention may be prepared. Compounds of formula (IA), (IB),(IC), (ID), or (IE), may be prepared by reduction of the correspondingketopyrrolidinylcyclohexyl ether compound with NaBH₄ in 2-propanol.Preparation of the starting aminoalcohol 2e requires the preparation ofamine 1e, for which suitable method of preparation is illustrated inFIG. 3. 3-Hydroxypyrrolidine 1a was N-protected by carbamoylation withbenzylchloroformate to give 1b, Swern oxidation (Mancuso, A. J.; Swern,D. Activated Dimethyl Sulfoxide Useful Reagents for Synthesis. Synthesis1981, 165-185) to 1c followed by ketalisation with ethylene glycolprovided 1d which was then hydrogenolyzed to give 1e.

The present invention provides synthetic processes whereby compounds offormula (57) with trans-(1R,2R) configuration for the ether and aminofunctional groups may be prepared in stereoisomerically substantiallypure form. Compounds of formulae (66), (67), (69) and (71) are some ofthe examples represented by formula (57). The present invention alsoprovides synthetic processes whereby compounds of formulae (52), (53),and (55) may be synthesized in stereoisomerically substantially pureforms. Compounds (61), (62) and (64) are examples of formulae (52), (53)and (55) respectively.

As outlined in FIG. 5, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by following a process starting from amonohalobenzene (49), wherein X may be F, Cl, Br or I.

In a first step, compound (49) is transformed by well-establishedmicrobial oxidation to the cis-cyclohexandienediol (50) instereoisomerically substantially pure form (T. Hudlicky et al.,Aldrichimica Acta, 1999, 32, 35; and references cited therein). In aseparate step, compound (50) may be selectively reduced under suitableconditions to compound (51) (e.g., H₂—Rh/Al₂O₃; Boyd et al. JCS Chem.Commun. 1996, 45-46; Ham and Coker, J. Org. Chem. 1964, 29, 194-198; andreferences cited therein). In another separate step, the less hinderedhydroxy group of formula (51) is selectively converted under suitableconditions into an activated form as represented by formula (52). An“activated form” as used herein means that the hydroxy group isconverted into a good leaving group (—O-J) which on reaction with anappropriate nucleophile will result in a substitution product withinversion of the stereochemical configuration. The leaving group may bea mesylate (MsO—) group, a tosylate group (TsO—) or a nosylate (NsO—),or other equivalent good leaving groups. The hydroxy group may also beconverted into other suitable leaving groups according to procedureswell known in the art. In a typical reaction for the formation of atosylate, compound (52) is treated with a hydroxy activating reagentsuch as tosyl chloride (TsCl) in the presence of a base, such aspyridine or triethylamine. The reaction is generally satisfactorilyconducted at about 0° C., but may be adjusted as required to maximizethe yields of the desired product. An excess of the hydroxy activatingreagent (e.g., tosyl chloride), relative to compound (52) may be used tomaximally convert the hydroxy group into the activated form. In aseparate step, transformation of compound (52) to compound (53) may beeffected by hydrogenation and hydrogenolysis in the presence of acatalyst under appropriate conditions. Palladium on activated carbon isone example of the catalysts. Hydrogenolysis of alkyl or alkenyl halidesuch as (52) may be conducted under basic conditions. The presence of abase such as sodium ethoxide, sodium bicarbonate, sodium acetate orcalcium carbonate is some possible examples. The base may be added inone portion or incrementally during the course of the reaction. In aseparate step, alkylation of the free hydroxy group in compound (53) toform compound (55) is carried out under appropriate conditions withcompound (54), where —O-Q represents a good leaving group on reactionwith a hydroxy function with retention of the stereochemicalconfiguration of the hydroxy function in the formation of an ethercompound. Trichloroacetimidate is one example for the —O-Q function. Forsome compound (54), it may be necessary to introduce appropriateprotection groups prior to this step being performed. Suitableprotecting groups are set forth in, for example, Greene, “ProtectiveGroups in Organic Chemistry”, John Wiley & Sons, New York N.Y. (1991).

In a separate step, the resulted compound (55) is treated under suitableconditions with an amino compound of formula (56) to form compound (57)as the product. The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (57) at a suitable rate. An excess of the aminocompound (56) may be used to maximally convert compound (55) to theproduct (57). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally the base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the product is recovered from the reactionmixture by conventional organic chemistry techniques, and is purifiedaccordingly. Protective groups may be removed at the appropriate stageof the reaction sequence. Suitable methods are set forth in, forexample, Greene, “Protective Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991).

The reaction sequence described above (FIG. 5) generates the compound offormula (57) as the free base. The free base may be converted, ifdesired, to the monohydrochloride salt by known methodologies, oralternatively, if desired, to other acid addition salts by reaction withan inorganic or organic acid under appropriate conditions. Acid additionsalts can also be prepared metathetically by reaction of one acidaddition salt with an acid that is stronger than that giving rise to theinitial salt.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application is specifically andindividually incorporated by reference.

In one embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (57):

wherein R₁ and R₂, when taken together with the nitrogen atom to whichthey are directly attached in formula (57), form a ring denoted byformula (II):

and R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen;

comprising the steps of starting with a monohalobenzene (49), wherein Xmay be F, Cl, Br or I; and following a reaction sequence as outlined inFIG. 5 under suitable conditions, wherein

—O-Q represents a good leaving group on reaction with a hydroxy functionwith retention of the stereochemical configuration of the hydroxyfunction in the formation of an ether compound; and

—O-J represents a good leaving group on reaction with a nucleophilicreactant with inversion of the stereochemical configuration as shown inFIG. 5 and all the formulae and symbols are as described above.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (66), comprising the steps under suitable conditions as shown inFIG. 6, wherein all the formulae and symbols are as described above. Asoutlined in FIG. 6, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by starting with a biotransformation of chlorobenzene(58) to compound (59) by microorganism such as Pseudomonas putida 39/D.Experimental conditions for the biotransformation are well established(Organic Synthesis, Vol. 76, 77 and T. Hudlicky et al., AldrichimicaActa, 1999, 32, 35; and references cited therein). In a separate step,compound (59) is selectively reduced under suitable conditions tocompound (60) (e.g., H₂—Rh/Al₂O₃; Boyd et al. JCS Chem. Commun. 1996,45-46; Ham and Coker, J. Org. Chem. 1964, 29, 194-198; and referencescited therein). In another separate step, the less hindered hydroxygroup of formula (60) is selectively converted under suitable conditionsinto an activated form such as the tosylate (TsO—) of formula (61)(e.g., TsCl in the presence of pyridine). In a separate step, compound(61) is converted to compound (62) by reduction such as hydrogenationand hydrogenolysis in the presence of a catalyst under appropriateconditions. Palladium on activated carbon is one example of thecatalysts. The reduction of compound (61) may be conducted under basicconditions e.g., in the presence of a base such as sodium ethoxide,sodium bicarbonate, sodium acetate or calcium carbonate. The base may beadded in one portion or incrementally during the course of the reaction.In another separate step, the free hydroxy group in compound (62) isalkylated under appropriate conditions to form compound (64). Thetrichloroacetimidate (63) is readily prepared from the correspondingalcohol, 3,4-dimethoxyphenethyl alcohol which is commercially available(e.g., Aldrich), by treatment with trichloroacetonitrile. The alkylationof compound (62) by trichloroacetimidate (63) may be carried out in thepresence of a Bronsted acid or Lewis acid such as HBF₄. In a separatestep, the tosylate group of formula (64) is displaced by an aminocompound such as 3R-pyrrolidinol (65) with inversion of configuration.3R-pyrrolidinol (65) is commercially available (e.g., Aldrich) or may beprepared according to published procedure (e.g., Chem. Ber./Recueil1997, 130, 385-397). The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (66) at a suitable rate. An excess of the aminocompound (65) may be used to maximally convert compound (64) to theproduct (66). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally theadditional base is non-nucleophilic in chemical reactivity. When thereaction has proceeded to substantial completion, the desired product isrecovered from the reaction mixture by conventional organic chemistrytechniques, and is purified accordingly.

The reaction sequence described above (FIG. 6) in general generates thecompound of formula (66) as the free base. The free base may beconverted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acid under appropriate conditions.Acid addition salts can also be prepared metathetically by reaction ofone acid addition salt with an acid that is stronger than that givingrise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 7, comprising the steps of starting from chlorobenzene (58) andfollowing a reaction sequence analogous to the applicable portion (i.e.,from compound (58) to compound (64)) that is described in FIG. 6 aboveleading to compound of formula (64). The latter is reacted undersuitable conditions with an amino compound of formula (65A) wherein Bnrepresents a benzyl protection group of the hydroxy function of3R-pyrrolidinol to form compound (67). Compound (65A) is commerciallyavailable (e.g., Aldrich) or may be prepared according to publishedprocedure (e.g., Chem. Ber./Recueil 1997, 130, 385-397). The reactionmay be carried out with or without a solvent and at an appropriatetemperature range that allows the formation of the product (67) at asuitable rate. An excess of the amino compound (65A) may be used tomaximally convert compound (64) to the product (67). The reaction may beperformed in the presence of a base that can facilitate the formation ofthe product. Generally the additional base is non-nucleophilic inchemical reactivity. The benzyl (Bn) protection group of compound (67)may be removed by standard procedure (e.g., hydrogenation in thepresence of a catalyst under appropriate conditions). Palladium onactivated carbon is one example of the catalysts. Other suitableconditions are as described in Greene, “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991)). The product is astereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (66) and is generally formed as the free base. Thefree base may be converted, if desired, to the monohydrochloride salt byknown methodologies, or alternatively, if desired, to other acidaddition salts by reaction with an inorganic or organic acids underappropriate conditions. Acid addition salts can also be preparedmetathetically by reaction of one acid addition salt with an acid thatis stronger than that giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 8, comprising the steps of starting from chlorobenzene (58) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 6 above leading to compound of formula (64). Thelatter is reacted with an amino compound of formula (68). Compound (68),3S-pyrrolidinol, is commercially available (e.g., Aldrich) or may beprepared according to published procedure (e.g., Chem. Ber./Recueil1997, 130, 385-397). The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (69) at a suitable rate. An excess of the aminocompound (68) may be used to maximally convert compound (64) to theproduct (69). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally theadditional base is non-nucleophilic in chemical reactivity. The productis a stereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (69) and is formed as the free base. The free basemay be converted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, if desired, to other acid additionsalts by reaction with an inorganic or organic acid under appropriateconditions. Acid addition salts can also be prepared metathetically byreaction of one acid addition salt with an acid that is stronger thanthat giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 9, comprising the steps of starting from chlorobenzene (58) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 7 above leading to compound of formula (64). Thelatter is reacted with an amino compound of formula (70) wherein Bnrepresents a benzyl protection group of the hydroxy function of3S-pyrrolidinol to form compound (71). Compound (70) is commerciallyavailable (e.g., Aldrich) or may be prepared according to publishedprocedure (e.g., Chem. Ber./Recueil 1997, 130, 385-397). The reactionmay be carried out with or without a solvent and at an appropriatetemperature range that allows the formation of the product (71) at asuitable rate. An excess of the amino compound (70) may be used tomaximally convert compound (64) to the product (71). The reaction may beperformed in the presence of a base that can facilitate the formation ofthe product. Generally the additional base is non-nucleophilic inchemical reactivity. The benzyl (Bn) protection group of compound (71)may be removed by standard procedure (e.g., hydrogenation in thepresence of a catalyst under appropriate conditions. Palladium onactivated carbon is one example of the catalysts. Other suitableconditions are as described in Greene, “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991)). The product is astereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (69) and is generally formed as the free base. Thefree base may be converted, if desired, to the monohydrochloride salt byknown methodologies, or alternatively, if desired, to other acidaddition salts by reaction with an inorganic or organic acids underappropriate conditions. Acid addition salts can also be preparedmetathetically by reaction of one acid addition salt with an acid thatis stronger than that giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 10, comprising the steps of starting with compound of formula (50)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 5, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 11, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 6, wherein all the formulae and symbols are asdescribed above. 3-Chloro-(1S,2S)-3,5-cyclohexadiene-1,2-diol of formula(59) is a commercially available product (e.g., Aldrich) or synthesizedaccording to published procedure (e.g., Organic Synthesis, Vol. 76, 77and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; and referencescited therein).

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 12, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 13, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 8, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 14, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 15, comprising the steps of starting with compound of formula (51)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 5, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 16, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 6, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 17, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 18, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 8, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 19, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 20, comprising the steps of starting with compound of formula (52)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 5, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 21, comprising the steps of starting with compound of formula (61)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 6, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 22, comprising the steps of starting with compound of formula (61)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 23, comprising the steps of starting with compound of formula (61)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 8, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 24, comprising the steps of starting with compound of formula (61)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 25, comprising the steps of starting with compound of formula (53)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 5, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 26, comprising the steps of starting with compound of formula (62)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 6, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 27, comprising the steps of starting with compound of formula (62)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 28, comprising the steps of starting with compound of formula (62)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 8, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 29, comprising the steps of starting with compound of formula (62)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 30, comprising the steps of starting with compound of formula (55)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 5, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 31, comprising the steps of starting with compound of formula (64)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 6, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 32, comprising the steps of starting with compound of formula (64)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 33, comprising the steps of starting with compound of formula (64)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 8, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 34, comprising the steps of starting with compound of formula (64)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 35, comprising the steps of starting with compound of formula (67)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out under suitable conditions by a process as outlined inFIG. 36, comprising the steps of starting with compound of formula (71)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (55) may be carried out undersuitable conditions by a process as outlined in FIG. 37, comprising thesteps of starting with compound of formula (49) and following a reactionsequence analogous to the applicable portion that is described in FIG.5, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (64) may be carried out undersuitable conditions by a process as outlined in FIG. 38, comprising thesteps of starting with compound of formula (58) and following a reactionsequence analogous to the applicable portion that is described in FIG.6, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (67)may be carried out under suitable conditions by a process as outlined inFIG. 39, comprising the steps of starting with compound of formula (58)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 7, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (71)may be carried out under suitable conditions by a process as outlined inFIG. 40, comprising the steps of starting with compound of formula (58)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 9, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (53) may be carried out undersuitable conditions by a process as outlined in FIG. 41, comprising thesteps of starting with compound of formula (49) and following a reactionsequence analogous to the applicable portion that is described in FIG.5, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (62) may be carried out undersuitable conditions by a process as outlined in FIG. 42, comprising thesteps of starting with compound of formula (58) and following a reactionsequence analogous to the applicable portion that is described in FIG.6, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (52) may be carried out undersuitable conditions by a process as outlined in FIG. 43, comprising thesteps of starting with compound of formula (49) and following a reactionsequence analogous to the applicable portion that is described in FIG.5, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (61) may be carried out undersuitable conditions by a process as outlined in FIG. 44, comprising thesteps of starting with compound of formula (58) and following a reactionsequence analogous to the applicable portion that is described in FIG.6, wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (52), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (53), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (54), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (55), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that when R₃, R₄ and R₅ are all hydrogen then J is not amethanesulfonyl group.

In another embodiment, the present invention provides a compound offormula (61), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (62), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (64), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (67), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides synthetic,processes whereby compounds of formula (75) with trans-(1S,2S)configuration for the ether and amino functional groups may be preparedin stereoisomerically substantially pure form. Compounds of formulae(79), (80), (81) and (82) are some of the examples represented byformula (75). The present invention also provides synthetic processeswhereby compounds of formulae (72), (73) and (74) may be synthesized instereoisomerically substantially pure forms. Compounds (76), (77) and(78) are examples of formulae (72), (73) and (74) respectively.

As outlined in FIG. 45, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out by following a process starting from amonohalobenzene (49), wherein X may be F, Cl, Br or I.

In a first step, compound (49) is transformed by well-establishedmicrobial oxidation to the cis-cyclohexandienediol (50) instereoisomerically substantially pure form (T. Hudlicky et al.,Aldrichimica Acta, 1999, 32, 35; and references cited therein). In aseparate step, compound (50) may be selectively reduced under suitableconditions to compound (51) (e.g., H₂—Rh/Al₂O₃; Boyd et al. JCS Chem.Commun. 1996, 45-46; Ham and Coker, J. Org. Chem. 1964, 29, 194-198; andreferences cited therein). In another separate step, compound (51) isconverted to compound (72) by reaction with compound (54) underappropriate conditions, where —O-Q represents a good leaving group onreaction with a hydroxy function with retention of the stereochemicalconfiguration of the hydroxy function in the formation of an ethercompound. Trichloroacetimidate is one example for the —O-Q function. Forsome compound (72), it may be necessary to introduce appropriateprotection groups prior to this step being performed. Suitableprotecting groups are set forth in, for example, Greene, “ProtectiveGroups in Organic Chemistry”, John Wiley & Sons, New York N.Y. (1991).

In a separate step, transformation of compound (72) to compound (73) maybe effected by hydrogenation and hydrogenolysis in the presence of acatalyst under appropriate conditions. Palladium on activated carbon isone example of the catalysts. Hydrogenolysis of alkyl or alkenyl halidesuch as (72) may be conducted under basic conditions. The presence of abase such as sodium ethoxide, sodium bicarbonate, sodium acetate orcalcium carbonate is some possible examples. The base may be added inone portion or incrementally during the course of the reaction. Inanother separate step, the hydroxy group of compound (73) is selectivelyconverted under suitable conditions into an activated form asrepresented by compound (74). An “activated form” as used herein meansthat the hydroxy group is converted into a good leaving group (—O-J)which on reaction with an appropriate nucleophile will result in asubstitution product with inversion of the stereochemical configuration.The leaving group may be a mesylate (MsO—) group, a tosylate group(TsO—) or a nosylate (NsO—). The hydroxy group may also be convertedinto other suitable leaving groups according to procedures well known inthe art. In a typical reaction for the formation of a tosylate, compound(73) is treated with a hydroxy activating reagent such as tosyl chloride(TsCl) in the presence of a base (e.g., pyridine or triethylamine). Thereaction is generally satisfactorily conducted at about 0° C., but maybe adjusted as required to maximize the yields of the desired product.An excess of the hydroxy activating reagent (e.g., tosyl chloride),relative to compound (73) may be used to maximally convert the hydroxygroup into the activated form.

In a separate step, the resulted compound (74) is treated under suitableconditions with an amino compound of formula (56) to form compound (75)as the product. The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (75) at a suitable rate. An excess of the aminocompound (56) may be used to maximally convert compound (74) to theproduct (75). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally the base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the product is recovered from the reactionmixture by conventional organic chemistry techniques, and is purifiedaccordingly. Protective groups may be removed at the appropriate stageof the reaction sequence. Suitable methods are set forth in, forexample, Greene, “Protective Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991).

The reaction sequence described above (FIG. 45) generates the compoundof formula (75) as the free base. The free base may be converted, ifdesired, to the monohydrochloride salt by known methodologies, oralternatively, if desired, to other acid addition salts by reaction withan inorganic or organic acid under appropriate conditions. Acid additionsalts can also be prepared metathetically by reaction of one acidaddition salt with an acid that is stronger than that giving rise to theinitial salt.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application is specifically andindividually incorporated by reference.

In one embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (75):

wherein R₁ and R₂, when taken together with the nitrogen atom to whichthey are directly attached in formula (75), form a ring denoted byformula (II):

and R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen;

comprising the steps of starting with a monohalobenzene (49), wherein Xmay be F, Cl, Br or I; and following a reaction sequence as outlined inFIG. 45 under suitable conditions, wherein

—O-Q represents a good leaving group on reaction with a hydroxy functionwith retention of the stereochemical configuration of the hydroxyfunction in the formation of an ether compound; and

—O-J represents a good leaving group on reaction with a nucleophilicreactant with inversion of the stereochemical configuration as shown inFIG. 45 and all the formulae and symbols are as described above.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (79), comprising the steps under suitable conditions as shown inFIG. 46, wherein all the formulae and symbols are as described above. Asoutlined in FIG. 46, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by starting with a biotransformation of chlorobenzene(58) to compound (59) by microorganism such as Pseudomonas putida 39/D.Experimental conditions for the biotransformation are well established(Organic Synthesis, Vol. 76, 77 and T. Hudlicky et al., AldrichimicaActa, 1999, 32, 35; and references cited therein). In a separate step,compound (59) is selectively reduced under suitable conditions tocompound (60) (e.g., H₂—Rh/Al₂O₃; Boyd et al. JCS Chem. Commun. 1996,45-46; Ham and Coker, J. Org. Chem. 1964, 29, 194-198; and referencescited therein). In another separate step, compound (60) is converted tocompound (76) by reaction with compound (63) under appropriateconditions. The trichloroacetimidate (63) is readily prepared from thecorresponding alcohol, 3,4-dimethoxyphenethyl alcohol which iscommercially available (e.g., Aldrich), by treatment withtrichloroacetonitrile. The alkylation of compound (60) bytrichloroacetimidate (63) may be carried out in the presence of aBronsted acid or Lewis acid such as HBF₄. The reaction temperature maybe adjusted as required to maximize the yields of the desired product.In a separate step, compound (76) is converted to compound (77) byreduction such as hydrogenation and hydrogenolysis in the presence of acatalyst under appropriate conditions. Palladium on activated carbon isone example of the catalysts. The reduction of compound (76) may beconducted under basic conditions e.g., in the presence of a base such assodium ethoxide, sodium bicarbonate, sodium acetate or calciumcarbonate. The base may be added in one portion or incrementally duringthe course of the reaction. In another separate step, the hydroxy groupof compound (77) is converted under suitable conditions into anactivated form such as the tosylate (TsO—) of formula (78) (e.g., TsClin the presence of pyridine). In a separate step, the tosylate group offormula (78) is displaced by an amino compound such as 3R-pyrrolidinol(65) with inversion of configuration. 3R-pyrrolidinol (65) iscommercially available (e.g., Aldrich) or may be prepared according topublished procedure (e.g., Chem. Ber./Recueil 1997, 130, 385-397). Thereaction may be carried out with or without a solvent and at anappropriate temperature range that allows the formation of the product(79) at a suitable rate. An excess of the amino compound (65) may beused to maximally convert compound (78) to the product (79). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

The reaction sequence described above (FIG. 46) in general generates thecompound of formula (79) as the free base. The free base may beconverted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acid under appropriate conditions.Acid addition salts can also be prepared metathetically by reaction ofone acid addition salt with an acid that is stronger than that givingrise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 47, comprising the steps of starting from chlorobenzene (58) andfollowing a reaction sequence analogous to the applicable portion (i.e.,from compound (58) to compound (78)) that is described in FIG. 46 aboveleading to compound of formula (78). The latter is reacted undersuitable conditions with an amino compound of formula (65A) wherein Bnrepresents a benzyl protection group of the hydroxy function of3S-pyrrolidinol to form compound (80). Compound (65A) is commerciallyavailable (e.g., Aldrich) or may be prepared according to publishedprocedure (e.g., Chem. Ber./Recueil 1997, 130, 385-397). The reactionmay be carried out with or without a solvent and at an appropriatetemperature range that allows the formation of the product (80) at asuitable rate. An excess of the amino compound (65A) may be used tomaximally convert compound (78) to the product (80). The reaction may beperformed in the presence of a base that can facilitate the formation ofthe product. Generally the additional base is non-nucleophilic inchemical reactivity. The benzyl (Bn) protection group of compound (80)may be removed by standard procedure (e.g., hydrogenation in thepresence of a catalyst under appropriate conditions. Palladium onactivated carbon is one example of the catalysts. Other suitableconditions are as described in Greene, “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991)). The product is astereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (79) and is generally formed as the free base. Thefree base may be converted, if desired, to the monohydrochloride salt byknown methodologies, or alternatively, if desired, to other acidaddition salts by reaction with an inorganic or organic acids underappropriate conditions. Acid addition salts can also be preparedmetathetically by reaction of one acid addition salt with an acid thatis stronger than that giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 48, comprising the steps of starting from chlorobenzene (58) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 46 above leading to compound of formula (78). Thelatter is reacted with an amino compound of formula (68). Compound (68),3S-pyrrolidinol, is commercially available (e.g., Aldrich) or may beprepared according to published procedure (e.g., Chem. Ber./Recueil1997, 130, 385-397). The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (81) at a suitable rate. An excess of the aminocompound (68) may be used to maximally convert compound (78) to theproduct (81). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally theadditional base is non-nucleophilic in chemical reactivity. The productis a stereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (81) and is formed as the free base. The free basemay be converted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, if desired, to other acid additionsalts by reaction with an inorganic or organic acid under appropriateconditions. Acid addition salts can also be prepared metathetically byreaction of one acid addition salt with an acid that is stronger thanthat giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 49, comprising the steps of starting from chlorobenzene (58) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 47 above leading to compound of formula (78). Thelatter is reacted with an amino compound of formula (70) wherein Bnrepresents a benzyl protection group of the hydroxy function of3S-pyrrolidinol to form compound (82). Compound (70) is commerciallyavailable (e.g., Aldrich) or may be prepared according to publishedprocedure (e.g., Chem. Ber./Recueil 1997, 130, 385-397). The reactionmay be carried out with or without a solvent and at an appropriatetemperature range that allows the formation of the product (82) at asuitable rate. An excess of the amino compound (70) may be used tomaximally convert compound (78) to the product (82). The reaction may beperformed in the presence of a base that can facilitate the formation ofthe product. Generally the additional base is non-nucleophilic inchemical reactivity. The benzyl (Bn) protection group of compound (82)may be removed by standard procedure (e.g., hydrogenation in thepresence of a catalyst under appropriate conditions. Palladium onactivated carbon is one example of the catalysts. Other suitableconditions are as described in Greene, “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991)). The product is astereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (81) and is generally formed as the free base. Thefree base may be converted, if desired, to the monohydrochloride salt byknown methodologies, or alternatively, if desired, to other acidaddition salts by reaction with an inorganic or organic acids underappropriate conditions. Acid addition salts can also be preparedmetathetically by reaction of one acid addition salt with an acid thatis stronger than that giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 50, comprising the steps of starting with compound of formula (50)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 45, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 51, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 46, wherein all the formulae and symbols areas described above. 3-Chloro-(1S,2S)-3,5-cyclohexadiene-1,2-diol offormula (59) is a commercially available product (e.g., Aldrich) orsynthesized according to published procedure (e.g., Organic Synthesis,Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; andreferences cited therein).

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 52, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 53, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 48, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 54, comprising the steps of starting with compound of formula (59)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 55, comprising the steps of starting with compound of formula (51)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 45, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 56, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 46, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 57, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 58, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 48, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 59, comprising the steps of starting with compound of formula (60)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 60, comprising the steps of starting with compound of formula (72)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 45, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 61, comprising the steps of starting with compound of formula (76)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 46, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 62, comprising the steps of starting with compound of formula (76)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 63, comprising the steps of starting with compound of formula (76)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 48, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 64, comprising the steps of starting with compound of formula (76)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 65, comprising the steps of starting with compound of formula (73)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 45, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 66, comprising the steps of starting with compound of formula (77)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 46, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 67, comprising the steps of starting with compound of formula (77)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 68, comprising the steps of starting with compound of formula (77)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 48, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 69, comprising the steps of starting with compound of formula (77)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 70, comprising the steps of starting with compound of formula (74)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 45, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 71, comprising the steps of starting with compound of formula (78)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 46, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 72, comprising the steps of starting with compound of formula (78)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 73, comprising the steps of starting with compound of formula (78)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 48, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 74, comprising the steps of starting with compound of formula (78)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 75, comprising the steps of starting with compound of formula (80)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out under suitable conditions by a process as outlined inFIG. 76, comprising the steps of starting with compound of formula (82)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (74) may be carried out undersuitable conditions by a process as outlined in FIG. 77, comprising thesteps of starting with compound of formula (49) and following a reactionsequence analogous to the applicable portion that is described in FIG.45, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (78) may be carried out undersuitable conditions by a process as outlined in FIG. 78, comprising thesteps of starting with compound of formula (58) and following a reactionsequence analogous to the applicable portion that is described in FIG.46, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (80)may be carried out under suitable conditions by a process as outlined inFIG. 79, comprising the steps of starting with compound of formula (58)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 47, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (82)may be carried out under suitable conditions by a process as outlined inFIG. 80, comprising the steps of starting with compound of formula (58)and following a reaction sequence analogous to the applicable portionthat is described in FIG. 49, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (73) may be carried out undersuitable conditions by a process as outlined in FIG. 81, comprising thesteps of starting with compound of formula (49) and following a reactionsequence analogous to the applicable portion that is described in FIG.45, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (77) may be carried out undersuitable conditions by a process as outlined in FIG. 82, comprising thesteps of starting with compound of formula (58) and following a reactionsequence analogous to the applicable portion that is described in FIG.46, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (72) may be carried out undersuitable conditions by a process as outlined in FIG. 83, comprising thesteps of starting with compound of formula (49) and following a reactionsequence analogous to the applicable portion that is described in FIG.45, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (76) may be carried out undersuitable conditions by a process as outlined in FIG. 84, comprising thesteps of starting with compound of formula (58) and following a reactionsequence analogous to the applicable portion that is described in FIG.46, wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (72), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (73), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (73), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (74), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that when R₃, R₄ and R₅ are all hydrogen then J is not amethanesulfonyl group.

In another embodiment, the present invention provides a compound offormula (76), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (77), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (78), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (80), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

The present invention provides synthetic processes whereby compounds offormula (57) with trans-(1R,2R) configuration for the ether and aminofunctional groups may be prepared in stereoisomerically substantiallypure form. Compound of formula (66) is an example represented by formula(57). The present invention also provides synthetic processes wherebycompounds of formula (75) with trans-(1S,2S) configuration for the etherand amino functional groups may be prepared in stereoisomericallysubstantially pure form. Compound of formula (79) is an examplerepresented by formula (75). The present invention further providessynthetic processes whereby compounds of formulae (85), (86), (55) and(74) may be synthesized in stereoisomerically substantially pure forms.Compounds (62) and (90) are examples of formula (85). Compounds (87) and(89) are examples of formula (86). Compound (64) is an example offormula (55). Compound (78) is an example of formula (74). Theaminocyclohexyl ether compounds of the present invention may be used formedical applications, including, for example, cardiac arrhythmia, suchas atrial arrhythmia and ventricular arrhythmia.

As outlined in FIG. 85, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by following a process starting from a racemicmixture of meso-cis-1,2-cyclohexandiol (83). Compound (83) iscommercially available (e.g., Sigma-Aldrich, St. Louis, Mo.) or can bereadily synthesized by published methods (e.g., J. E. Taylor et al.,Org. Process Res. & Dev., 1998, 2, 147; Organic Syntheses, CV6, 342).

In a first step, one of the hydroxy groups of compound (83) is convertedunder suitable conditions into an activated form as represented by theracemic mixture comprised of formulae (53) and (84). An “activated form”as used herein means that the hydroxy group is converted into a goodleaving group (—O-J) which on reaction with an appropriate nucleophilewill result in a substitution product with inversion of thestereochemical configuration. The leaving group may be any suitableleaving group on reaction with a nucleophilic reactant with inversion ofstereochemical configuration known in the art, including but not limitedto compounds disclosed in M. B. Smith and J. March in “March's AdvancedOrganic Chemistry”, Fifth edition, Chapter 10, John Wiley & Sons, Inc.,New York, N.Y. (2001). Specific examples of such leaving groups includea mesylate (MsO—) group, a tosylate group (TsO—), a2-bromophenylsulfonate group, a 4-bromophenylsulfonate group or anosylate (NsO—) group. The hydroxy group may also be converted intoother suitable leaving groups according to procedures well known in theart, using any suitable activating agent, including but not limited tothose disclosed in M. B. Smith and J. March in “March's Advanced OrganicChemistry”, Fifth edition, Chapter 10, John Wiley & Sons, Inc., NewYork, N.Y. (2001). In a typical reaction for the formation of atosylate, compound (83) is treated with a controlled amount of hydroxyactivating reagent such as tosyl chloride (TsCl) in the presence of abase, such as pyridine or triethylamine. The reaction may be monitoredand is generally satisfactorily conducted at about 0° C., but conditionsmay be adjusted as required to maximize the yields of the desiredproduct. The addition of other reagents to facilitate the formation ofthe monotosylates may be advantageously employed (e.g., M. J.Martinelli, et al. “Selective monosulfonylation of internal 1,2-diolscatalyzed by di-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773).The racemic mixture comprises of formulae (53) and (84) is thensubjected to a resolution process whereby the two optically activeisomers are separated into products that are in stereoisomericallysubstantially pure form such as (85) and (86), wherein G and G₁ areindependently selected from hydrogen, C₁-C₈acyl, or any other suitablefunctional groups that are introduced as part of the resolution processnecessary for the separation of the two isomers. In some situations itmay be adequate that the resolution process produces compounds of (85)and (86) of sufficient enrichment in their optical purity forapplication in the subsequent steps of the synthetic process. Methodsfor resolution of racemic mixtures are well know in the art (e.g., E. L.Eliel and S. H. Wilen, in Stereochemistry of Organic Compounds; JohnWiley & Sons: New York, 1994; Chapter 7, and references cited therein).Suitable processes such as enzymatic resolution (e.g., lipase mediated)and chromatographic separation (e.g., HPLC with chiral stationary phaseand/or with simulated moving bed technology) are some of the examplesthat may be applied.

For compound of formula (85) when G is hydrogen, (85) is the same ascompound (53) and in a separate reaction step, alkylation of the freehydroxy group in compound (85) to form compound (55) is carried outunder appropriate conditions with compound (54), where —O-Q represents agood leaving group on reaction with a hydroxy function with retention ofthe stereochemical configuration of the hydroxy function in theformation of an ether compound. The leaving group may be any suitableleaving group known in the art, including but not limited to compoundsdisclosed in Greene, “Protective Groups in Organic Chemistry”, JohnWiley & Sons, New York N.Y. (1991). Specific examples of -0-Q groupsinclude trichloroacetimidate. For some compound (54), it may benecessary to introduce appropriate protection groups prior to this stepbeing performed. Suitable protecting groups are set forth in, forexample, Greene, “Protective Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991). For compound of formula (85) when G is nothydrogen, suitable methods are used to convert (85) to compound (53).For example when G is a C₂ acyl function, a mild based-catalyzedmethanolysis (G. Zemplen et al., Ber., 1936, 69, 1827) may be used totransform (85) to (53). The latter can then undergo the same reactionwith (54) to produce (55) as described above.

In a separate step, the resulted compound (55) is treated under suitableconditions with an amino compound of formula (56) to form compound (57)as the product. The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (57) at a suitable rate. An excess of the aminocompound (56) may be used to maximally convert compound (55) to theproduct (57). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally the base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the product is recovered from the reactionmixture by conventional organic chemistry techniques, and is purifiedaccordingly. Protective groups may be removed at the appropriate stageof the reaction sequence. Suitable methods are set forth in, forexample, Greene, “Protective. Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991).

The reaction sequence described above (FIG. 85) generates the compoundof formula (57) as the free base. The free base may be converted, ifdesired, to the monohydrochloride salt by known methodologies, oralternatively, if desired, to other acid addition salts by reaction withan inorganic or organic acid under appropriate conditions. Acid additionsalts can also be prepared metathetically by reaction of one acidaddition salt with an acid that is stronger than that giving rise to theinitial salt.

In one embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (57):

wherein R₁ and R₂, when taken together with the nitrogen atom to whichthey are directly attached in formula (57), form a ring denoted byformula (II):

and R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen;

comprising the steps of starting with a monohalobenzene (49), wherein Xmay be F, Cl, Br or I; and following a reaction sequence as outlined inFIG. 45 under suitable conditions, wherein

—O-Q represents a good leaving group on reaction with a hydroxy functionwith retention of the stereochemical configuration of the hydroxyfunction in the formation of an ether compound; and

—O-J represents a good leaving group on reaction with a nucleophilicreactant with inversion of the stereochemical configuration as shown inFIG. 45 and all the formulae and symbols are as described above,comprising the steps of starting with a compound of formula (83), andfollowing a reaction sequence as outlined in FIG. 85 under suitableconditions, wherein

G and G₁ are independently selected from hydrogen, C₁-C₈acyl, or anyother suitable functional groups that are introduced as part of theresolution process necessary for the separation of the two isomers;

—O-Q represents a good leaving group on reaction with a hydroxy functionwith retention of the stereochemical configuration of the hydroxyfunction in the formation of an ether compound, including, but notlimited to, those disclosed in “Protective Groups in Organic Chemistry”,John Wiley & Sons, New York N.Y. (1991); and

—O-J represents a good leaving group on reaction with a nucleophilicreactant with inversion of the stereochemical configuration, including,but not limited to, those disclosed in “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991), as shown in FIG. 85and all the formulae and symbols are as described above.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (66), comprising the steps under suitable conditions as shown inFIG. 86, wherein all the formulae and symbols are as described above. Asoutlined in FIG. 86, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by starting with the monotosylation ofcis-1,2-cyclohexandiol (83) with TsCl in the presence of Bu₂SnO andtriethylamine under suitable conditions (M. J. Martinelli, et al.“Selective monosulfonylation of internal 1,2-diols catalyzed bydi-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773). Initialnon-optimized yields of 80-90% have been achieved, and furtheroptimization is being pursued. The resulting racemic mixture ofhydroxytosylates comprises of compounds (62) and (87) is subjected to alipase-mediated resolution process under suitable conditions such astreatment of the racemates (62) and (87) with vinyl acetate (88) in thepresence of a lipase derived from Pseudomonas sp. (N. Boaz et al.,Tetra. Asymmetry, 1994, 5, 153) to provide compound (62) and (89). In aseparate step, the stereoisomerically substantially pure compound offormula (62) obtained from the resolution process is alkylated underappropriate conditions by treatment with the trichloroacetimidate (63)to form compound (64). Initial non-optimized yields of 60-70% have beenachieved, and further optimization is being pursued. Thetrichloroacetimidate (63) is readily prepared from the correspondingalcohol, 3,4-dimethoxyphenethyl alcohol which is commercially available(e.g., Sigma-Aldrich, St. Louis, Mo.), by treatment withtrichloroacetonitrile. The alkylation of compound (62) bytrichloroacetimidate (63) may be carried out in the presence of a Lewisacid such as HBF₄.

In another separate step, the tosylate group of formula (64) isdisplaced by an amino compound such as 3R-pyrrolidinol (65) withinversion of configuration. 3R-pyrrolidinol (65) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (66) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (64) to the product (66). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly. Initial non-optimized yields of approximately 40%have been achieved, and further optimization is being pursued.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 87, comprising the steps under suitable conditions as shown in FIG.87, wherein all the formulae and symbols are as described above. Asoutlined in FIG. 87, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by starting with the monotosylation of thecis-1,2-cyclohexandiol (83) with TsCl in the presence of Bu₂SnO andtriethylamine under suitable conditions (M. J. Martinelli, et al.“Selective monosulfonylation of internal 1,2-diols catalyzed bydi-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773). The resultingracemic mixture of hydroxytosylates comprises of compounds (62) and (87)is subjected to a lipase-mediated resolution process under suitableconditions such as treatment of the racemates (62) and (87) with vinylacetate (88) in the presence of a lipase derived from Pseudomonas sp.(N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) to provide compound(90) and (87).

In a separate step, the stereoisomerically substantially pure compoundof formula (90) obtained from the resolution process is subjected to amild based-catalyzed methanolysis (G. Zemplen et al., Ber., 1936, 69,1827) to form compound (62). The latter is alkylated under appropriateconditions by treatment with the trichloroacetimidate (63) to formcompound (64). The trichloroacetimidate (63) is readily prepared fromthe corresponding alcohol, 3,4-dimethoxyphenethyl alcohol which iscommercially available (e.g., Sigma-Aldrich, St. Louis, Mo.), bytreatment with trichloroacetonitrile. The alkylation of compound (88) bytrichloroacetimidate (63) may be carried out in the presence of a Lewisacid such as HBF₄.

In another separate step, the tosylate group of formula (64) isdisplaced by an amino compound such as 3R-pyrrolidinol (65) withinversion of configuration. 3R-pyrrolidinol (65) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (66) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (64) to the product (66). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (66), comprising the steps under suitable conditions as shown inFIG. 88, wherein all the formulae and symbols are as described above. Asoutlined in FIG. 88, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by starting with the monotosylation of thecis-1,2-cyclohexandiol (83) with TsCl in the presence of Bu₂SnO andtriethylamine under suitable conditions (M. J. Martinelli, et al.“Selective monosulfonylation of internal 1,2-diols catalyzed bydi-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773). The resultingracemic mixture of hydroxytosylates comprises of compounds (62) and (87)is subjected to a chromatographic resolution process under suitableconditions such as HPLC with an appropriate chiral stationary phase andsimulated moving bed technology to provide compounds (62) and (87) instereoisomerically substantially pure form.

In a separate step, the stereoisomerically substantially pure compoundof formula (62) obtained from the resolution process is alkylated underappropriate conditions by treatment with the trichloroacetimidate (63)to form compound (64). The trichloroacetimidate (63) is readily preparedfrom the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol which iscommercially available (e.g., Sigma-Aldrich, St. Louis, Mo.), bytreatment with trichloroacetonitrile. The alkylation of compound (62) bytrichloroacetimidate (63) may be carried out in the presence of a Lewisacid such as HBF₄.

In another separate step, the tosylate group of formula (64) isdisplaced by an amino compound such as 3R-pyrrolidinol (65) withinversion of configuration. 3R-pyrrolidinol (65) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (66) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (64) to the product (66). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

The reaction sequences described above (FIG. 86, FIG. 87 and FIG. 88) ingeneral generate the compound of formula (66) as the free base. The freebase may be converted, if desired, to the monohydrochloride salt byknown methodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acid under appropriate conditions.Acid addition salts can also be prepared metathetically by reaction ofone acid addition salt with an acid that is stronger than that givingrise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 89, comprising the steps of starting with a racemic mixturecomprises of formulae (53) and (84) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 85,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 90, comprising the steps of starting with a racemic mixturecomprises of formulae (62) and (87) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 86,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 91, comprising the steps of starting with a racemic mixturecomprises of formulae (62) and (87) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 87,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 92, comprising the steps of starting with a racemic mixturecomprises of formulae (62) and (87) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 88,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out under suitable conditions by a process as outlined inFIG. 93, comprising the steps of starting with a compound of formula(85) where G is not hydrogen and following a reaction sequence analogousto the applicable portion that is described in FIG. 85, wherein all theformulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out under suitable conditions by a process as outlined inFIG. 94, comprising the steps of starting with a compound of formula(90) and following a reaction sequence analogous to the applicableportion that is described in FIG. 87, wherein all the formulae andsymbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (55) may be carried out undersuitable conditions by a process as outlined in FIG. 95, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.85, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (55) may be carried out undersuitable conditions by a process as outlined in FIG. 96, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.85, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (64) may be carried out undersuitable conditions by a process as outlined in FIG. 97, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.86, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (64) may be carried out undersuitable conditions by a process as outlined in FIG. 98, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.87, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (64) may be carried out undersuitable conditions by a process as outlined in FIG. 99, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.88, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of stereoisomericallysubstantially pure compounds of formulae (85) and (86) may be carriedout under suitable conditions by a process as outlined in FIG. 100,comprising the steps of starting with compound of formula (83) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 85, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of stereoisomericallysubstantially pure compounds of formulae (62) and (89) may be carriedout under suitable conditions by a process as outlined in FIG. 101,comprising the steps of starting with compound of formula (83) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 86, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of stereoisomericallysubstantially pure compounds of formulae (90) and (87) may be carriedout under suitable conditions by a process as outlined in FIG. 102,comprising the steps of starting with compound of formula (83) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 87, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of stereoisomericallysubstantially pure compounds of formulae (62) and (87) may be carriedout under suitable conditions by a process as outlined in FIG. 103,comprising the steps of starting with compound of formula (83) andfollowing a reaction sequence analogous to the applicable portion thatis described in FIG. 88, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the present invention further provides syntheticprocesses whereby compounds of formula (75) with trans-(1S,2S)configuration for the ether and amino functional groups may be preparedin stereoisomerically substantially pure form. As outlined in FIG. 104,the preparation of a stereoisomerically substantially pure transaminocyclohexyl ether compound of formula (75) may be carried out byfollowing a process starting from a racemic mixture ofmeso-cis-1,2-cyclohexandiol (83). Compound (83) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or can be readilysynthesized by published methods (e.g., J. E. Taylor et al., Org.Process Res. & Dev., 1998, 2, 147; Organic Syntheses, CV6, 342).

In a first step, one of the hydroxy groups of compound (83) is convertedunder suitable conditions into an activated form as represented by theracemic mixture comprised of formulae (53) and (84). An “activated form”as used herein means that the hydroxy group is converted into a goodleaving group (—O-J) which on reaction with an appropriate nucleophilewill result in a substitution product with inversion of thestereochemical configuration. The leaving group may be any suitableleaving group on reaction with a nucleophilic reactant with inversion ofstereochemical configuration known in the art, including but not limitedto compounds disclosed in M. B. Smith and J. March in “March's AdvancedOrganic Chemistry”, Fifth edition, Chapter 10, John Wiley & Sons, Inc.,New York, N.Y. (2001). Specific examples of such leaving groups includea mesylate (MsO—) group, a tosylate group (TsO—), a2-bromophenylsulfonate group, a 4-bromophenylsulfonate group or anosylate (NsO—) group. The hydroxy group may also be converted intoother suitable leaving groups according to procedures well known in theart, using any suitable activating agent, including but not limited tothose disclosed in M. B. Smith and J. March in “March's Advanced OrganicChemistry”, Fifth edition, Chapter 10, John Wiley & Sons, Inc., NewYork, N.Y. (2001). In a typical reaction for the formation of atosylate, compound (83) is treated with a controlled amount of hydroxyactivating reagent such as tosyl chloride (TsCl) in the presence of abase, such as pyridine or triethylamine. The reaction may be monitoredand is generally satisfactorily conducted at about 0° C., but conditionsmay be adjusted as required to maximize the yields of the desiredproduct. The addition of other reagents to facilitate the formation ofthe monotosylates may be advantageously employed (e.g., M. J.Martinelli, et al. “Selective monosulfonylation of internal 1,2-diolscatalyzed by di-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773).The racemic mixture comprises of formulae (53) and (84) is thensubjected to a resolution process whereby the two optically activeisomers are separated into products that are in stereoisomericallysubstantially pure form such as (85) and (86), wherein G and G₁ areindependently selected from hydrogen, C₁-C₈acyl, or any other suitablefunctional groups that are introduced as part of the resolution processnecessary for the separation of the two isomers. In some situations itmay be adequate that the resolution process produces compounds of (85)and (86) of sufficient enrichment in their optical purity forapplication in the subsequent steps of the synthetic process. Methodsfor resolution of racemic mixtures are well know in the art (e.g., E. L.Eliel and S. H. Wilen, in Stereochemistry of Organic Compounds; JohnWiley & Sons: New York, 1994; Chapter 7, and references cited therein).Suitable processes such as enzymatic resolution (e.g., lipase mediated)and chromatographic separation (e.g., HPLC with chiral stationary phaseand/or with simulated moving bed technology) are some of the methodsthat may be applied.

For compound of formula (86) when G₁ is hydrogen, (86) is the same ascompound (84) and in a separate reaction step, alkylation of the freehydroxy group in compound (86) to form compound (74) is carried outunder appropriate conditions with compound (54), where —O-Q represents agood leaving group on reaction with a hydroxy function with retention ofthe stereochemical configuration of the hydroxy function in theformation of an ether compound. The leaving group may be any suitableleaving group known in the art, including but not limited to compoundsdisclosed in Greene, “Protective Groups in Organic Chemistry”, JohnWiley & Sons, New York N.Y. (1991). Trichloroacetimidate is one examplefor the —O-Q function. For some compound (54), it may be necessary tointroduce appropriate protection groups prior to this step beingperformed. Suitable protecting groups are set forth in, for example,Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, NewYork N.Y. (1991). For compound of formula (86) when G₁ is not hydrogen,suitable methods are used to convert (86) to compound (84). For examplewhen G₁ is a C₂ acyl function, a mild based-catalyzed methanolysis (G.Zemplen et al., Ber., 1936, 69, 1827) may be used to transform (86) to(84). The latter can then undergo the same reaction with (54) to produce(74) as described above.

In a separate step, the resulted compound (74) is treated under suitableconditions with an amino compound of formula (56) to form compound (75)as the product. The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (75) at a suitable rate. An excess of the aminocompound (56) may be used to maximally convert compound (74) to theproduct (75). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally the base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the product is recovered from the reactionmixture by conventional organic chemistry techniques, and is purifiedaccordingly. Protective groups may be removed at the appropriate stageof the reaction sequence. Suitable methods are set forth in, forexample, Greene, “Protective Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991).

The reaction sequence described above (FIG. 104) generates the compoundof formula (75) as the free base. The free base may be converted, ifdesired, to the monohydrochloride salt by known methodologies, oralternatively, if desired, to other acid addition salts by reaction withan inorganic or organic acid under appropriate conditions. Acid additionsalts can also be prepared metathetically by reaction of one acidaddition salt with an acid that is stronger than that giving rise to theinitial salt.

In one embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (75):

wherein R₁ and R₂, when taken together with the nitrogen atom to whichthey are directly attached in formula (75), form a ring denoted byformula (II):

and R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen;

comprising the steps of starting with a compound of formula (83), andfollowing a reaction sequence as outlined in FIG. 104 under suitableconditions, wherein

G and G₁ are independently selected from hydrogen, C₁-C₈acyl, or anyother suitable functional groups that are introduced as part of theresolution process necessary for the separation of the two isomers;

—O-Q represents a good leaving group on reaction with a hydroxy functionwith retention of the stereochemical configuration of the hydroxyfunction in the formation of an ether compound, including, but notlimited to, those disclosed in “Protective Groups in Organic Chemistry”,John Wiley & Sons, New York N.Y. (1991); and

—O-J represents a good leaving group on reaction with a nucleophilicreactant with inversion of the stereochemical configuration, including,but not limited to, those disclosed in “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991), as shown in FIG.104 and all the formulae and symbols are as described above.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (79), comprising the steps under suitable conditions as shown inFIG. 105, wherein all the formulae and symbols are as described above.As outlined in FIG. 105, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by starting with the monotosylation ofcis-1,2-cyclohexandiol (83) with TsCl in the presence of Bu₂SnO andtriethylamine under suitable conditions (M. J. Martinelli, et al.“Selective monosulfonylation of internal 1,2-diols catalyzed bydi-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773). The resultingracemic mixture of hydroxytosylates comprises of compounds (62) and (87)is subjected to a lipase-mediated resolution process under suitableconditions such as treatment of the racemates (62) and (87) with vinylacetate (88) in the presence of a lipase derived from Pseudomonas sp.(N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) to provide compound(87) and (90). In a separate step, the stereoisomerically substantiallypure compound of formula (87) obtained from the resolution process isalkylated under appropriate conditions by treatment with thetrichloroacetimidate (63) to form compound (78). Thetrichloroacetimidate (63) is readily prepared from the correspondingalcohol, 3,4-dimethoxyphenethyl alcohol which is commercially available(e.g., Sigma-Aldrich, St. Louis, Mo.), by treatment withtrichloroacetonitrile. The alkylation of compound (87) bytrichloroacetimidate (63) may be carried out in the presence of a Lewisacid such as HBF₄.

In another separate step, the tosylate group of formula (78) isdisplaced by an amino compound such as 3R-pyrrolidinol (65) withinversion of configuration. 3R-pyrrolidinol (65) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (79) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (78) to the product (79). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 106, comprising the steps under suitable conditions as shown inFIG. 106, wherein all the formulae and symbols are as described above.As outlined in FIG. 106, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by starting with the monotosylation of thecis-1,2-cyclohexandiol (83) with TsCl in the presence of Bu₂SnO andtriethylamine under suitable conditions (M. J. Martinelli, et al.“Selective monosulfonylation of internal 1,2-diols catalyzed bydi-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773). The resultingracemic mixture of hydroxytosylates comprises of compounds (62) and (87)is subjected to a lipase-mediated resolution process under suitableconditions such as treatment of the racemates (62) and (87) with vinylacetate (88) in the presence of a lipase derived from Pseudomonas sp.(N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) to provide compound(89) and (62).

In a separate step, the stereoisomerically substantially pure compoundof formula (89) obtained from the resolution process is subjected to amild based-catalyzed methanolysis (G. Zemplen et al., Ber., 1936, 69,1827) to form compound (87). The latter is alkylated under appropriateconditions by treatment with the trichloroacetimidate (63) to formcompound (78). The trichloroacetimidate (63) is readily prepared fromthe corresponding alcohol, 3,4-dimethoxyphenethyl alcohol which iscommercially available (e.g., Sigma-Aldrich, St. Louis, Mo.), bytreatment with trichloroacetonitrile. The alkylation of compound (87) bytrichloroacetimidate (63) may be carried out in the presence of a Lewisacid such as HBF₄.

In another separate step, the tosylate group of formula (78) isdisplaced by an amino compound such as 3R-pyrrolidinol (65) withinversion of configuration. 3R-pyrrolidinol (65) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (79) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (78) to the product (79). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (79), comprising the steps under suitable conditions as shown inFIG. 107, wherein all the formulae and symbols are as described above.As outlined in FIG. 107, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by starting with the monotosylation of thecis-1,2-cyclohexandiol (83) with TsCl in the presence of Bu₂SnO andtriethylamine under suitable conditions (M. J. Martinelli, et al.“Selective monosulfonylation of internal 1,2-diols catalyzed bydi-n-butyltin oxide” Tetrahedron Letters, 2000, 41, 3773). The resultingracemic mixture of hydroxytosylates comprises of compounds (62) and (87)is subjected to a chromatographic resolution process under suitableconditions such as HPLC with an appropriate chiral stationary phase andsimulated moving bed technology to provide compounds (62) and (87) instereoisomerically substantially pure form.

In a separate step, the stereoisomerically substantially pure compoundof formula (87) obtained from the resolution process is alkylated underappropriate conditions by treatment with the trichloroacetimidate (63)to form compound (64). The trichloroacetimidate (63) is readily preparedfrom the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol which iscommercially available (e.g., Sigma-Aldrich, St. Louis, Mo.), bytreatment with trichloroacetonitrile. The alkylation of compound (87) bytrichloroacetimidate (63) may be carried out in the presence of a Lewisacid such as HBF₄.

In another separate step, the tosylate group of formula (78) isdisplaced by an amino compound such as 3R-pyrrolidinol (65) withinversion of configuration. 3R-pyrrolidinol (65) is commerciallyavailable (e.g., Sigma-Aldrich, St. Louis, Mo.) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (79) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (78) to the product (79). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

The reaction sequences described above (FIG. 105, FIG. 106 and FIG. 107)in general generate the compound of formula (79) as the free base. Thefree base may be converted, if desired, to the monohydrochloride salt byknown methodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acid under appropriate conditions.Acid addition salts can also be prepared metathetically by reaction ofone acid addition salt with an acid that is stronger than that givingrise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 108, comprising the steps of starting with a racemic mixturecomprises of formulae (53) and (84) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 104,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 109, comprising the steps of starting with a racemic mixturecomprises of formulae (62) and (87) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 105,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 110, comprising the steps of starting with a racemic mixturecomprises of formulae (62) and (87) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 106,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 111, comprising the steps of starting with a racemic mixturecomprises of formulae (62) and (87) and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 107,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 112, comprising the steps of starting with a compound of formula(86) where G₁ is hydrogen and following a reaction sequence analogous tothe applicable portion that is described in FIG. 104, wherein all theformulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out under suitable conditions by a process as outlined inFIG. 113, comprising the steps of starting with a compound of formula(86) where G₁ is not hydrogen and following a reaction sequenceanalogous to the applicable portion that is described in FIG. 104,wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 114, comprising the steps of starting with a compound of formula(87) and following a reaction sequence analogous to the applicableportion that is described in FIG. 105, wherein all the formulae andsymbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out under suitable conditions by a process as outlined inFIG. 115, comprising the steps of starting with a compound of formula(89) and following a reaction sequence analogous to the applicableportion that is described in FIG. 106, wherein all the formulae andsymbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (74) may be carried out undersuitable conditions by a process as outlined in FIG. 116, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.104, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (74) may be carried out undersuitable conditions by a process as outlined in FIG. 117, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.104, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (78) may be carried out undersuitable conditions by a process as outlined in FIG. 118, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.105, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (78) may be carried out undersuitable conditions by a process as outlined in FIG. 119, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.106, wherein all the formulae and symbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (78) may be carried out undersuitable conditions by a process as outlined in FIG. 120, comprising thesteps of starting with compound of formula (83) and following a reactionsequence analogous to the applicable portion that is described in FIG.107, wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (85), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (86), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (54), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (55), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that when R₃, R₄ and R₅ are all hydrogen then J is not amethanesulfonyl group.

In another embodiment, the present invention provides a compound offormula (87), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention, provides a compound offormula (62), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (89), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (90), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (64), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (74), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that when R₃, R₄ and R₅ are all hydrogen then J is not amethanesulfonyl group.

In another embodiment, the present invention provides a compound offormula (78), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In one embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (57):

wherein R₁ and R₂, when taken together with the nitrogen atom to whichthey are directly attached in formula (57), form a ring denoted byformula (II):

and R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen;

comprising the steps of starting with a monohalobenzene (49), wherein Xmay be F, Cl, Br or I; and following a reaction sequence as outlined inFIG. 121 under suitable conditions, wherein

Pro represents the appropriate protecting group of the hydroxy functionwith retention of stereochemistry;

—O-Q represents a good leaving group on reaction with a hydroxy functionwith retention of the stereochemical configuration of the hydroxyfunction in the formation of an ether compound; and

—O-J represents a good leaving group on reaction with a nucleophilicreactant with inversion of the stereochemical configuration asillustrated in FIG. 121 and all the formulae and symbols are asdescribed above.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (66), comprising the steps under suitable conditions as shown inFIG. 122, wherein all the formulae and symbols are as described above.As outlined in FIG. 122, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by starting with a biotransformation of chlorobenzene(58) to compound (59) by microorganism such as Pseudomonas putida 39/D.Experimental conditions for the biotransformation are well established(Organic Synthesis, Vol. 76, 77 and T. Hudlicky et al., AldrichimicaActa, 1999, 32, 35; and references cited therein). In a separate step,the less hindered hydroxy function in compound (59) is selectivelymonosilylated as compound (95) by reaction with silylating reagent suchas t-butyldiphenylsilyl chloride (TBDPSCl) under suitable conditions(e.g., imaidazole in CH₂Cl₂) (T. Hudlicky et al., Aldrichimica Acta,1999, 32, 35; S. M. Brown and T. Hudlicky, In Organic Synthesis: Theoryand Applications; T. Hudlicky, Ed.; JAI Press: Greenwich, Conn., 1993;Vol. 2, p 113; and references cited therein). In another separate step,compound (95) is converted to compound (96) by reduction such ashydrogenation and hydrogenolysis in the presence of a catalyst underappropriate conditions. Palladium on activated carbon is one example ofthe catalysts. The reduction of compound (95) may be conducted underbasic conditions, e.g., in the presence of a base such as sodiumethoxide, sodium bicarbonate, sodium acetate or calcium carbonate. Thebase may be added in one portion or incrementally during the course ofthe reaction. In a separate step, the free hydroxy group in compound(96) is alkylated under appropriate conditions to form compound (97).The trichloroacetimidate (63) is readily prepared from the correspondingalcohol, 3,4-dimethoxyphenethyl alcohol which is commercially available(e.g., Aldrich), by treatment with trichloroacetonitrile. The alkylationof compound (96) by trichloroacetimidate (63) may be carried out in thepresence of a Lewis acid such as HBF₄. In another separate step, thet-butyldiphenylsilyl (TBDPS) protection group in compound (97) may beremoved by standard procedures (e.g., tetrabutylammonium fluoride intetrahydrofuran (THF) or as described in Greene, “Protective Groups inOrganic Chemistry”, John Wiley & Sons, New York N.Y. (1991)) to affordthe hydroxyether compound (98). In a separate step, the hydroxy group ofcompound (98) is converted under suitable conditions into an activatedform such as the tosylate of formula (64). In another separate step, thetosylate group of formula (64) is displaced by an amino compound such as3R-pyrrolidinol (65) with inversion of configuration. 3R-pyrrolidinol(65) is commercially available (e.g., Aldrich) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (66) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (64) to the product (66). Thereaction may be performed in the presence of a base that can facilitatethe formation of the product. Generally the additional base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the desired product is recovered from thereaction mixture by conventional organic chemistry techniques, and ispurified accordingly.

The reaction sequence described above (FIG. 122) in general generatesthe compound of formula (66) as the free base. The free base may beconverted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acid under appropriate conditions.Acid addition salts can also be prepared metathetically by reaction ofone acid addition salt with an acid that is stronger than that givingrise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out by a process as outlined in FIG. 123, comprising thesteps of starting with chlorobenzene (58) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 122 above leading to compound of formula (64).The latter is reacted with an amino compound of formula (68). Compound(68), 3S-pyrrolidinol, is commercially available (e.g., Aldrich) or maybe prepared according to published procedure (e.g., Chem. Ber./Recueil1997, 130, 385-397). The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (69) at a suitable rate. An excess of the aminocompound (68) may be used to maximally convert compound (64) to theproduct (69). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally theadditional base is non-nucleophilic in chemical reactivity. The productis a stereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (69) and is formed as the free base. The free basemay be converted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, if desired, to other acid additionsalts by reaction with an inorganic or organic acids under appropriateconditions. Acid addition salts can also be prepared metathetically byreaction of one acid addition salt with an acid that is stronger thanthat giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by a process as outlined in FIG. 124, comprising thesteps of starting with compound of formula (50) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 121, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by a process as outlined in FIG. 125, comprising thesteps of starting with compound of formula (59) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 122, wherein all the formulae and symbols areas described above. 3-Chloro-(1S,2S)-3,5-cyclohexadiene-1,2-diol offormula (59) is a commercially available product (e.g., Aldrich) orsynthesized according to published procedure (e.g., Organic Synthesis,Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; andreferences cited therein).

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out by a process as outlined in FIG. 126, comprising thesteps of starting with compound of formula (59) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 123, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by a process as outlined in FIG. 127, comprising thesteps of starting with compound of formula (91) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 121, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by a process as outlined in FIG. 128, comprising thesteps of starting with compound of formula (95) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 122, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out by a process as outlined in FIG. 129, comprising thesteps of starting with compound of formula (95) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 123, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by a process as outlined in FIG. 130, comprising thesteps of starting with compound of formula (92) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 121, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by a process as outlined in FIG. 131, comprising thesteps of starting with compound of formula (96) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 122, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out by a process as outlined in FIG. 132, comprising thesteps of starting with compound of formula (96) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 123, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by a process as outlined in FIG. 133, comprising thesteps of starting with compound of formula (93) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 121, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by a process as outlined in FIG. 134, comprising thesteps of starting with compound of formula (97) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 122, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out by a process as outlined in FIG. 135, comprising thesteps of starting with compound of formula (97) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 123, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (57)may be carried out by a process as outlined in FIG. 136, comprising thesteps of starting with compound of formula (94) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 121, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (66)may be carried out by a process as outlined in FIG. 137, comprising thesteps of starting with compound of formula (98) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 122, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (69)may be carried out by a process as outlined in FIG. 138, comprising thesteps of starting with compound of formula (98) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 123, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (55) may be carried out by aprocess as outlined in FIG. 139, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 121, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (64) may be carried out by aprocess as outlined in FIG. 140, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 122, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (94) may be carried out by aprocess as outlined in FIG. 141, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 121, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (98) may be carried out by aprocess as outlined in FIG. 142, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 122, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (93) may be carried out by aprocess as outlined in FIG. 143, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 121, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (97) may be carried out by aprocess as outlined in FIG. 144, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 122, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (92) may be carried out by aprocess as outlined in FIG. 145, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 121, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (96) may be carried out by aprocess as outlined in FIG. 146, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 122, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the present invention provides a compound offormula (92), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (54), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (93), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (94), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (55), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that when R₃, R₄ and R₅ are all hydrogen then J is not amethanesulfonyl group.

In another embodiment, the present invention provides a compound offormula (96), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (63), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (97), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (98), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (64), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

The present invention provides synthetic processes whereby compounds offormula (75) with trans-(1S,2S) configuration for the ether and aminofunctional groups may be prepared in stereoisomerically substantiallypure form. Compounds of formulae (79) and (81) are some of the examplesrepresented by formula (75). The present invention also providessynthetic processes whereby compounds of formulae (92), (99), (84) and(74) may be synthesized in stereoisomerically substantially pure forms.Compounds (96), (100), (62) and (78) are examples of formulae (92),(99), (84) and (74), respectively.

As outlined in FIG. 147, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out by following a process starting with amonohalobenzene (49), wherein X may be F, Cl, Br or I.

In a first step, compound (49) is transformed by well-establishedmicrobial oxidation to the cis-cyclohexandienediol (50) instereoisomerically substantially pure form (T. Hudlicky et al.,Aldrichimica Acta, 1999, 32, 35; and references cited therein). In aseparate step, the less hindered hydroxy function in compound (50) maybe selectively monoprotected as compound (91) where Pro represents theappropriate protecting group of the hydroxy function with retention ofstereochemistry (T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; S.M. Brown and T. Hudlicky, In Organic Synthesis: Theory and Applications;T. Hudlicky, Ed.; JAI Press: Greenwich, Conn., 1993; Vol. 2, p 113; andreferences cited therein). Tri-alkyl-silyl groups such astri-isopropyl-silyl (TIPS) and t-butyldimethylsilyl (TBDMS) andalkyl-diaryl-silyl groups such as t-butyldiphenylsilyl (TBDPS) are someof the possible examples for Pro. Suitable reaction conditions are setforth in, for example, Greene, “Protective Groups in Organic Chemistry”,John Wiley & Sons, New York N.Y. (1991). In a separate step, conversionof compound (91) to compound (92) may be effected by hydrogenation andhydrogenolysis in the presence of a catalyst under appropriateconditions. Palladium on activated carbon is one example of thecatalysts. Hydrogenolysis of alkyl or alkenyl halide such as (91) may beconducted under basic conditions. The presence of a base such as sodiumethoxide, sodium bicarbonate, sodium acetate or calcium carbonate issome possible examples. The base may be added in one portion orincrementally during the course of the reaction. In a separate step, thefree hydroxy group of compound (92) is converted into an activated formas represented by formula (99) under suitable conditions. An “activatedform” as used herein means that the hydroxy group is converted into agood leaving group (—O-J). The leaving group may be a mesylate (MsO—)group, a tosylate group (TsO—) or a nosylate (NsO—). The hydroxy groupmay also be converted into other suitable leaving groups according toprocedures well known in the art. In a typical reaction for theformation of a tosylate, compound (92) is treated with a hydroxyactivating reagent such as tosyl chloride (TsCl) in the presence of abase, such as pyridine or triethylamine. The reaction is generallysatisfactorily conducted at about 0° C., but may be adjusted as requiredto maximize the yields of the desired product. An excess of the hydroxyactivating reagent (e.g., tosyl chloride), relative to compound (92) maybe used to maximally convert the hydroxy group into the activated form.In a separate step, removal of the protecting group (Pro) in compound(99) by standard procedures (e.g., tetrabutylammonium fluoride intetrahydrofuran or as described in Greene, “Protective Groups in OrganicChemistry”, John Wiley & Sons, New York N.Y. (1991)) affords compound(84). In a separate step, alkylation of the free hydroxy group incompound (84) to form compound (74) is carried out under appropriateconditions with compound (54), where —O-Q represents a good leavinggroup on reaction with a hydroxy function with retention of thestereochemical configuration of the hydroxy function in the formation ofan ether compound. Trichloroacetimidate is one example for the —O-Qfunction. For some compound (54), it may be necessary to introduceappropriate protection groups prior to this step being performed.Suitable protecting groups are set forth in, for example, Greene,“Protective Groups in Organic Chemistry”, John Wiley & Sons, New YorkN.Y. (1991).

In a separate step, the resulted compound (74) is treated under suitableconditions with an amino compound of formula (56) to form compound (75)as the product. The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (75) at a suitable rate. An excess of the aminocompound (56) may be used to maximally convert compound (74) to theproduct (75). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally the base isnon-nucleophilic in chemical reactivity. When the reaction has proceededto substantial completion, the product is recovered from the reactionmixture by conventional organic chemistry techniques, and is purifiedaccordingly. Protective groups may be removed at the appropriate stageof the reaction sequence. Suitable methods are set forth in, forexample, Greene, “Protective Groups in Organic Chemistry”, John Wiley &Sons, New York N.Y. (1991).

The reaction sequence described above (FIG. 147) generates the compoundof formula (75) as the free base. The free base may be converted, ifdesired, to the monohydrochloride salt by known methodologies, oralternatively, to other acid addition salts by reaction with aninorganic or organic acid under appropriate conditions. Acid additionsalts can also be prepared metathetically by reaction of one acidaddition salt with an acid that is stronger than that giving rise to theinitial salt.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application is specifically andindividually incorporated by reference.

In one embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (75):

wherein R₁ and R₂, when taken together with the nitrogen atom to whichthey are directly attached in formula (75), form a ring denoted byformula (II):

and R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy andC₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen;

comprising the steps of starting with a monohalobenzene (49), wherein Xmay be F, Cl, Br or I; and following a reaction sequence as outlined inFIG. 147 under suitable conditions, wherein

Pro represents the appropriate protecting group of the hydroxy functionwith retention of stereochemistry;

—O-Q represents a good leaving group on reaction with a hydroxy functionunder suitable conditions with retention of the stereochemicalconfiguration of the hydroxy function in the formation of an ethercompound; and

—O-J represents a good leaving group on reaction with a nucleophilicreactant under suitable conditions with inversion of the stereochemicalconfiguration as illustrated in FIG. 147 and all the formulae andsymbols are as described above.

In another embodiment, the present invention provides a process for thepreparation of a stereoisomerically substantially pure compound offormula (79), comprising the steps under suitable conditions as shown inFIG. 148, wherein all the formulae and symbols are as described above.As outlined in FIG. 148, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by starting with a biotransformation of chlorobenzene(49) to compound (59) by microorganism such as Pseudomonas putida 39/D.Experimental conditions for the biotransformation are well established(Organic Synthesis, Vol. 76, 77 and T. Hudlicky et al., AldrichimicaActa, 1999, 32, 35; and references cited therein). In a separate step,the less hindered hydroxy function in compound (59) is selectivelymonosilylated as compound (95) by reaction with silylating reagent suchas t-butyldiphenylsilyl chloride (TBDPSCl) under suitable conditions(e.g., imaidazole in CH₂Cl₂) (T. Hudlicky et al., Aldrichimica Acta,1999, 32, 35; S. M. Brown and T. Hudlicky, In Organic Synthesis: Theoryand Applications; T. Hudlicky, Ed.; JAI Press: Greenwich, Conn., 1993;Vol. 2, p 113; and references cited therein). In another separate step,compound (95) is converted to compound (96) by reduction such ashydrogenation and hydrogenolysis in the presence of a catalyst underappropriate conditions. Palladium on activated carbon is one example ofthe catalysts. The reduction of compound (95) may be conducted underbasic conditions e.g., in the presence of a base such as sodiumethoxide, sodium bicarbonate, sodium acetate or calcium carbonate. Thebase may be added in one portion or incrementally during the course ofthe reaction. In a separate step, the hydroxy group of compound (96) isconverted under suitable conditions into an activated form such as thetosylate of formula (100) by treatment with tosyl chloride (TsCl) in thepresence of pyridine. In another separate step, the t-butyldiphenylsilyl(TBDPS) protection group in compound (100) may be removed by standardprocedures (e.g., tetrabutylammonium fluoride in tetrahydrofuran or asdescribed in Greene, “Protective Groups in Organic Chemistry”, JohnWiley & Sons, New York N.Y. (1991)) to afford the hydroxytosylatecompound (62). In a separate step, the free hydroxy group in compound(62) is alkylated under appropriate conditions to form compound (78).The trichloroacetimidate (63) is readily prepared from the correspondingalcohol, 3,4-dimethoxyphenethyl alcohol which is commercially available(e.g., Aldrich), by treatment with trichloroacetonitrile. The alkylationof compound (62) by trichloroacetimidate (63) may be carried out in thepresence of a Lewis acid such as HBF₄. In another separate step, thetosylate group of formula (78) is displaced by an amino compound such as3R-pyrrolidinol (65) with inversion of configuration. 3R-pyrrolidinol(65) is commercially available (e.g., Aldrich) or may be preparedaccording to published procedure (e.g., Chem. Ber./Recueil 1997, 130,385-397). The reaction may be carried out with or without a solvent andat an appropriate temperature range that allows the formation of theproduct (79) at a suitable rate. An excess of the amino compound (65)may be used to maximally convert compound (78) to the product (79). Thereaction may be performed in the presence of a base that can facilitatethe formation and isolation of the product. Generally the additionalbase is non-nucleophilic in chemical reactivity. When the reaction hasproceeded to substantial completion, the desired product is recoveredfrom the reaction mixture by conventional organic chemistry techniques,and is purified accordingly.

The reaction sequence described above (FIG. 148) in general generatesthe compound of formula (79) as the free base. The free base may beconverted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acid under appropriate conditions.Acid addition salts can also be prepared metathetically by reaction ofone acid addition salt with an acid that is stronger than that givingrise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out by a process as outlined in FIG. 149, comprising thesteps of starting with chlorobenzene (58) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 148 above leading to compound of formula (78).The latter is reacted with an amino compound of formula (68). Compound(68), 3S-pyrrolidinol, is commercially available (e.g., Aldrich) or maybe prepared according to published procedure (e.g., Chem. Ber./Recueil1997, 130, 385-397). The reaction may be carried out with or without asolvent and at an appropriate temperature range that allows theformation of the product (81) at a suitable rate. An excess of the aminocompound (68) may be used to maximally convert compound (78) to theproduct (81). The reaction may be performed in the presence of a basethat can facilitate the formation of the product. Generally theadditional base is non-nucleophilic in chemical reactivity. The productis a stereoisomerically substantially pure trans aminocyclohexyl ethercompound of formula (81) and is formed as the free base. The free basemay be converted, if desired, to the monohydrochloride salt by knownmethodologies, or alternatively, to other acid addition salts byreaction with an inorganic or organic acids under appropriateconditions. Acid addition salts can also be prepared metathetically byreaction of one acid addition salt with an acid that is stronger thanthat giving rise to the initial salt.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out by a process as outlined in FIG. 150, comprising thesteps of starting with compound of formula (50) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 147, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by a process as outlined in FIG. 151, comprising thesteps of starting with compound of formula (59) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 148, wherein all the formulae and symbols areas described above. 3-Chloro-(1S,2S)-3,5-cyclohexadiene-1,2-diol offormula (59) is a commercially available product (e.g., Aldrich) orsynthesized according to published procedure (e.g., Organic Synthesis,Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; andreferences cited therein).

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out by a process as outlined in FIG. 152, comprising thesteps of starting with compound of formula (59) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 149, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out by a process as outlined in FIG. 153, comprising thesteps of starting with compound of formula (91) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 147, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by a process as outlined in FIG. 154, comprising thesteps of starting with compound of formula (95) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 148, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out by a process as outlined in FIG. 155, comprising thesteps of starting with compound of formula (95) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 149, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out by a process as outlined in FIG. 156, comprising thesteps of starting with compound of formula (92) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 147, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by a process as outlined in FIG. 157, comprising thesteps of starting with compound of formula (96) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 148, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out by a process as outlined in FIG. 158, comprising thesteps of starting with compound of formula (96) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 149, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (75)may be carried out by a process as outlined in FIG. 159, comprising thesteps of starting with compound of formula (99) and following a reactionsequence under suitable conditions analogous to the applicable portionthat is described in FIG. 147, wherein all the formulae and symbols areas described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (79)may be carried out by a process as outlined in FIG. 160, comprising thesteps of starting with compound of formula (100) and following areaction sequence under suitable conditions analogous to the applicableportion that is described in FIG. 148, wherein all the formulae andsymbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure trans aminocyclohexyl ether compound of formula (81)may be carried out by a process as outlined in FIG. 161, comprising thesteps of starting with compound of formula (100) and following areaction sequence under suitable conditions analogous to the applicableportion that is described in FIG. 149, wherein all the formulae andsymbols are as described above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (74) may be carried out by aprocess as outlined in FIG. 162, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 147, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (78) may be carried out by aprocess as outlined in FIG. 163, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 148, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (84) may be carried out by aprocess as outlined in FIG. 164, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 147, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (62) may be carried out by aprocess as outlined in FIG. 165, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 148, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (99) may be carried out by aprocess as outlined in FIG. 166, comprising the steps of starting withcompound of formula (49) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 147, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the preparation of a stereoisomericallysubstantially pure compound of formula (100) may be carried out by aprocess as outlined in FIG. 167, comprising the steps of starting withcompound of formula (58) and following a reaction sequence undersuitable conditions analogous to the applicable portion that isdescribed in FIG. 148, wherein all the formulae and symbols are asdescribed above.

In another embodiment, the present invention provides a compound offormula (92), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (99), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (84), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (54), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that R₃, R₄ and R₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound offormula (74), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above with theproviso that when R₃, R₄ and R₅ are all hydrogen then J is not amethanesulfonyl group.

In another embodiment, the present invention provides a compound offormula (96), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (100), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (62), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (63), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

In another embodiment, the present invention provides a compound offormula (78), or a solvate or pharmaceutically acceptable salt thereof;wherein all the formulae and symbols are as described above.

The reaction sequences described above (FIG. 1 and FIG. 2) generate theaminocyclohexyl ether compounds of the present invention as the freebase initially. The free base may be converted, if desired, to themonohydrochloride salt by known methodologies, or alternatively, ifdesired, to other acid addition salts by reaction with the appropriateinorganic or organic acids. Acid addition salts can also be preparedmetathetically by reaction of one acid addition salt with an acid thatis stronger than that giving rise to the initial salt.

It is recognized that there may be one or more chiral centers in thecompounds used within the scope of the present invention and thus suchcompounds will exist as various stereoisomeric forms. Applicants intendto include all the various stereoisomers within the scope of theinvention. Though the compounds may be prepared as racemates and canconveniently be used as such, individual enantiomers also can beisolated or preferentially synthesized by known techniques if desired.Such racemates and individual enantiomers and mixtures thereof areintended to be included within the scope of the present invention. Pureenantiomeric forms if produced may be isolated by preparative chiralHPLC. The free base may be converted if desired, to themonohydrochloride salt by known methodologies, or alternatively, ifdesired, to other acid addition salts by reaction with other inorganicor organic acids. Acid addition salts can also be preparedmetathetically by reacting one acid addition salt with an acid that isstronger than that of the anion of the initial salt.

The present invention also encompasses the pharmaceutically acceptablesalts, esters, amides, complexes, chelates, solvates; crystalline oramorphous forms, metabolites, metabolic precursors or prodrugs of thecompounds of the present invention. Pharmaceutically acceptable estersand amides can be prepared by reacting, respectively, a hydroxy or aminofunctional group with a pharmaceutically acceptable organic acid, suchas identified below. A prodrug is a drug which has been chemicallymodified and may be biologically inactive at its site of action, butwhich is degraded or modified by one or more enzymatic or other in vivoprocesses to the parent bioactive form. Generally, a prodrug has adifferent pharmakokinetic profile than the parent drug such that, forexample, it is more easily absorbed across the mucosal epithelium, ithas better salt formation or solubility and/or it has better systemicstability (e.g., an increased plasma half-life).

Those skilled in the art recognize that chemical modifications of aparent drug to yield a prodrug include: (1) terminal ester or amidederivatives which are susceptible to being cleaved by esterases orlipases; (2) terminal peptides which may be recognized by specific ornonspecific proteases; or (3) a derivative that causes the prodrug toaccumulate at a site of action through membrane selection, andcombinations of the above techniques. Conventional procedures for theselection and preparation of prodrug derivatives are described in H.Bundgaard, Design of Prodrugs, (1985). Those skilled in the art arewell-versed in the preparation of prodrugs and are well-aware of itsmeaning.

The present invention also encompasses the pharmaceutically acceptablecomplexes, chelates, metabolites, or metabolic precursors of thecompounds of the present invention. Information about the meaning theseterms and references to their preparation can be obtained by searchingvarious databases, for example Chemical Abstracts and the U.S. Food andDrug Administration (FDA) website. Documents such as the followings areavailable from the FDA: Guidance for Industry, “In Vivo DrugMetabolism/Drug Interaction Studies—Study Design, Data Analysis, andRecommendations for Dosing and Labeling”, U.S. Department of Health andHuman Services, Food and Drug Administration, Center for Drug Evaluationand Research (CDER), Center for Biologics Evaluation and Research(CBER), November 1999. Guidance for Industry, “In Vivo DrugMetabolism/Drug Interaction Studies in the DRUG DEVELOPMENT PROCESS:STUDIES IN VITRO”, U.S. Department of Health and Human Services, Foodand Drug Administration, Center for Drug Evaluation and Research (CDER),Center for Biologics Evaluation and Research (CBER), April 1997.

The synthetic procedures described herein, especially when taken withthe general knowledge in the art, provide sufficient guidance to thoseof ordinary skill in the art to perform the synthesis, isolation, andpurification of the compounds of the present invention.

Compositions and Modes of Administration

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from any of thecompounds or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof, described above, incombination with a pharmaceutically acceptable carrier, diluent orexcipient, and further provides a method for the manufacture of such acomposition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof, in combination with a pharmaceutically acceptable carrier,diluent or excipient, and further provides a method for the manufactureof such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, or metabolite thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof, in combination with a pharmaceutically acceptable carrier,diluent or excipient, and further provides a method for the manufactureof such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

in combination with a pharmaceutically acceptable carrier, diluent orexcipient, and further provides a method for the manufacture of such acomposition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

in combination with a pharmaceutically acceptable carrier, diluent orexcipient, and further provides a method for the manufacture of such acomposition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; in combinationwith a pharmaceutically acceptable carrier, diluent or excipient, andfurther provides a method for the manufacture of such a composition ormedicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination with apharmaceutically acceptable carrier, diluent or excipient, and furtherprovides a method for the manufacture of such a composition ormedicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds of the present inventionaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, or metabolite thereof,in combination with appropriate amounts of sodium chloride USP, citricacid USP, sodium hydroxide NF and water for injection USP; and furtherprovides a method for the manufacture of such a composition ormedicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxycyclohexane free base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; in combinationwith appropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP; and further provides a methodfor the manufacture of such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination withappropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP; and further provides a methodfor the manufacture of such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds of the present inventionaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, or metabolite thereof,in combination with appropriate amounts of sodium chloride USP, citricacid USP, sodium hydroxide NF and water for injection USP that resultedin an isotonic intravenous solution of said compound at a concentrationof about 0.1 mg/ml to 100 mg/ml in sodium citrate of about 1 to 400 mMat a pH of about 7.5 to 4.0; and further provides a method for themanufacture of such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; in combinationwith appropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 0.1mg/ml to 100 mg/ml in sodium citrate of about 1 to 400 mM at a pH ofabout 7.5 to 4.0; and further provides a method for the manufacture ofsuch a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination withappropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 0.1mg/ml to 100 mg/ml in sodium citrate of about 1 to 400 mM at a pH ofabout 7.5 to 4.0; and further provides a method for the manufacture ofsuch a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds of the present inventionaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, or metabolite thereof,in combination with appropriate amounts of sodium chloride USP, citricacid USP, sodium hydroxide NF and water for injection USP that resultedin an isotonic intravenous solution of said compound at a concentrationof about 5 mg/ml to 80 mg/ml in sodium citrate of about 10 to 80 mM at apH of about 6.5 to 4.5; and further provides a method for themanufacture of such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; in combinationwith appropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 5mg/ml to 80 mg/ml in sodium citrate of about 10 to 80 mM at a pH ofabout 6.5 to 4.5; and further provides a method for the manufacture ofsuch a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination withappropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 5mg/ml to 80 mg/ml in sodium citrate of about 10 to 80 mM at a pH ofabout 6.5 to 4.5; and further provides a method for the manufacture ofsuch a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds of the present inventionaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, or metabolite thereof,in combination with appropriate amounts of sodium chloride USP, citricacid USP, sodium hydroxide NF and water for injection USP that resultedin an isotonic intravenous solution of said compound at a concentrationof about 10 mg/ml to 40 mg/ml in sodium citrate of about 20 to 60 mM ata pH of about 6 to 5; and further provides a method for the manufactureof such a composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; in combinationwith appropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 10mg/ml to 40 mg/ml in sodium citrate of about 20 to 60 mM at a pH ofabout 6 to 5; and further provides a method for the manufacture of sucha composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination withappropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 10mg/ml to 40 mg/ml in sodium citrate of about 20 to 60 mM at a pH ofabout 6 to 5; and further provides a method for the manufacture of sucha composition or medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds of the present inventionaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, or metabolite thereof,in combination with appropriate amounts of sodium chloride USP, citricacid USP, sodium hydroxide NF and water for injection USP that resultedin an isotonic intravenous solution of said compound at a concentrationof about 20 mg/ml in sodium citrate of about 40 mM at a pH of about 5.5;and further provides a method for the manufacture of such a compositionor medicament.

In other embodiments, the present invention provides a composition ormedicament that includes one or more compounds, selected from the groupconsisting of:

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; in combinationwith appropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 20mg/ml in sodium citrate of about 40 mM at a pH of about 5.5; and furtherprovides a method for the manufacture of such a composition ormedicament.

In other embodiments, the present invention provides a composition ormedicament that includes a compound which is(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride, or any solvate thereof; in combination withappropriate amounts of sodium chloride USP, citric acid USP, sodiumhydroxide NF and water for injection USP that resulted in an isotonicintravenous solution of said compound at a concentration of about 20mg/ml in sodium citrate of about 40 mM at a pH of about 5.5; and furtherprovides a method for the manufacture of such a composition ormedicament.

In another embodiment, the present invention provides compositions whichinclude a compound of the present invention in admixture or otherwise inassociation with one or more inert carriers, excipients and diluents, aswell as optional ingredients if desired. These compositions are usefulas, for example, assay standards, convenient means of making bulkshipments, or pharmaceutical compositions. An assayable amount of acompound of the invention is an amount which is readily measurable bystandard assay procedures and techniques as are well known andappreciated by those skilled in the art. Assayable amounts of a compoundof the invention will generally vary from about 0.001 wt % to about 75wt % of the entire weight of the composition. Inert carriers include anymaterial which does not degrade or otherwise covalently react with acompound of the invention. Examples of suitable inert carriers arewater; aqueous buffers, such as those which are generally useful in HighPerformance Liquid Chromatography (HPLC) analysis; organic solvents suchas acetonitrile, ethyl acetate, hexane and the like (which are suitablefor use in in vitro diagnostics or assays, but typically are notsuitable for administration to a warm-blooded animal); andpharmaceutically acceptable carriers, such as physiological saline.

Thus, the present invention provides a pharmaceutical or veterinarycomposition (hereinafter, simply referred to as a pharmaceuticalcomposition) containing a compound of the present invention, inadmixture with a pharmaceutically acceptable carrier, excipient ordiluent. The invention further provides a pharmaceutical compositioncontaining an effective amount of compound of the present invention, inassociation with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be in anyform which allows for the composition to be administered to a patient.For example, the composition may be in the form of a solid, liquid orgas (aerosol). Typical routes of administration include, withoutlimitation, oral, topical, parenteral, sublingual, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, epidural, intrasternal injectionor infusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a patient take the form of oneor more dosage units, where for example, a tablet, capsule or cachet maybe a single dosage unit, and a container of the compound in aerosol formmay hold a plurality of dosage units.

Materials used in preparing the pharmaceutical compositions should bepharmaceutically pure and non-toxic in the amounts used. The inventivecompositions may include one or more compounds (active ingredients)known for a particularly desirable effect. It will be evident to thoseof ordinary skill in the art that the optimal dosage of the activeingredient(s) in the pharmaceutical composition will depend on a varietyof factors. Relevant factors include, without limitation, the type ofsubject (e.g., human), the particular form of the active ingredient, themanner of administration and the composition employed.

In general, the pharmaceutical composition includes a compound of thepresent invention as described herein, in admixture with one or morecarriers. The carrier(s) may be particulate, so that the compositionsare, for example, in tablet or powder form. The carrier(s) may beliquid, with the compositions being, for example, an oral syrup orinjectable liquid. In addition, the carrier(s) may be gaseous, so as toprovide an aerosol composition useful in, e.g., inhalatoryadministration.

When intended for oral administration, the composition is preferably ineither solid or liquid form, where semi-solid, semi-liquid, suspensionand gel forms are included within the forms considered herein as eithersolid or liquid.

As a solid composition for oral administration, the composition may beformulated into a powder, granule, compressed tablet, pill, capsule,cachet, chewing gum, wafer, lozenges, or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following adjuvants may bepresent: binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone,carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gumtragacanth or gelatin, and mixtures thereof; excipients such as starch,lactose or dextrins, disintegrating agents such as alginic acid, sodiumalginate, Primogel, corn starch and the like; lubricants such asmagnesium stearate or Sterotex; fillers such as lactose, mannitols,starch, calcium phosphate, sorbitol, methylcellulose, and mixturesthereof; lubricants such as magnesium stearate, high molecular weightpolymers such as polyethylene glycol, high molecular weight fatty acidssuch as stearic acid, silica, wetting agents such as sodium laurylsulfate, glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin, a flavoring agent such as peppermint,methyl salicylate or orange flavoring, and a coloring agent.

When the composition is in the form of a capsule, e.g., a gelatincapsule, it may contain, in addition to materials of the above type, aliquid carrier such as polyethylene glycol or a fatty oil.

The composition may be in the form of a liquid, e.g., an elixir, syrup,solution, aqueous or oily emulsion or suspension, or even dry powderswhich may be reconstituted with water and/or other liquid media prior touse. The liquid may be for oral administration or for delivery byinjection, as two examples. When intended for oral administration,preferred compositions contain, in addition to the present compounds,one or more of a sweetening agent, thickening agent, preservative (e.g.,alkyl p-hydroxybenzoate), dye/colorant and flavor enhancer (flavorant).In a composition intended to be administered by injection, one or moreof a surfactant, preservative (e.g., alkyl p-hydroxybenzoate), wettingagent, dispersing agent, suspending agent (e.g., sorbitol, glucose, orother sugar syrups), buffer, stabilizer and isotonic agent may beincluded. The emulsifying agent may be selected from lecithin orsorbitol monooleate.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordigylcerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid composition intended for either parenteral or oraladministration should contain an amount of the inventive compound suchthat a suitable dosage will be obtained. Typically, this amount is atleast 0.01% of a compound of the invention in the composition. Whenintended for oral administration, this amount may be varied to bebetween 0.1 and about 70% of the weight of the composition. Preferredoral compositions contain between about 4% and about 50% of the activeaminocyclohexyl ether compound. Preferred compositions and preparationsaccording to the present invention are prepared so that a parenteraldosage unit contains between 0.01 to 10% by weight of active compound.

The pharmaceutical composition may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment, cream or gel base. The base, for example,may comprise one or more of the following: petrolatum, lanolin,polyethylene glycols, bee wax, mineral oil, diluents such as water andalcohol, and emulsifiers and stabilizers. Thickening agents may bepresent in a pharmaceutical composition for topical administration. Ifintended for transdermal administration, the composition may include atransdermal patch or iontophoresis device. Topical formulations maycontain a concentration of the inventive compound of from about 0.1 toabout 25% w/v (weight per unit volume).

The composition may be intended for rectal administration, in the form,e.g., of a suppository which will melt in the rectum and release thedrug. The composition for rectal administration may contain anoleaginous base as a suitable nonirritating excipient. Such basesinclude, without limitation, lanolin, cocoa butter and polyethyleneglycol. Low-melting waxes are preferred for the preparation of asuppository, where mixtures of fatty acid glycerides and/or cocoa butterare suitable waxes. The waxes may be melted, and the aminocyclohexylether compound is dispersed homogeneously therein by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool and thereby solidify.

The composition may include various materials which modify the physicalform of a solid or liquid dosage unit. For example, the composition mayinclude materials that form a coating shell around the activeingredients. The materials which form the coating shell are typicallyinert and may be selected from, for example, sugar, shellac, and otherenteric coating agents. Alternatively, the active ingredients may beencased in a gelatin capsule or cachet.

The composition in solid or liquid form may include an agent which bindsto the aminocyclohexyl ether compound and thereby assists in thedelivery of the active components. Suitable agents which may act in thiscapacity include a monoclonal or polyclonal antibody, a protein or aliposome.

The pharmaceutical composition of the present invention may consist ofgaseous dosage units, e.g., it may be in the form of an aerosol. Theterm aerosol is used to denote a variety of systems ranging from thoseof colloidal nature to systems consisting of pressurized packages.Delivery may be by a liquefied or compressed gas or by a suitable pumpsystem which dispenses the active ingredients. Aerosols of compounds ofthe invention may be delivered in single phase, bi-phasic, or tri-phasicsystems in order to deliver the active ingredient(s). Delivery of theaerosol includes the necessary container, activators, valves,subcontainers, and the like, which together may form a kit. Preferredaerosols may be determined by one skilled in the art, without undueexperimentation.

Whether in solid, liquid or gaseous form, the pharmaceutical compositionof the present invention may contain one or more known pharmacologicalagents used in methods for either modulating ion channel activity in awarm-blooded animal or for modulating ion channel activity in vitro, orused in the treatment and/or prevention of arrhythmia includingatrial/supraventricular arrhythmia and ventricular arrhythmia, atrialfibrillation, ventricular fibrillation, atrial flutter, ventricularflutter, diseases of the central nervous system, convulsion,cardiovascular diseases (e.g., diseases caused by elevated bloodcholesterol or triglyceride levels), cerebral or myocardial ischemias,hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases,diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis,paramyotonia congentia, malignant hyperthermia, hyperkalemic periodicparalysis, Thomsen's myotonia, autoimmune disorders, graft rejection inorgan transplantation or bone marrow transplantation, heart failure,hypotension, Alzheimer's disease, dementia and other mental disorders,alopecia, sexual dysfunction, impotence, demyelinating diseases,multiple sclerosis, amyotrophic lateral sclerosis, epileptic spasms,depression, anxiety, schizophrenia, Parkinson's disease, respiratorydisorders, cystic fibrosis, asthma, cough, inflammation, arthritis,allergies, urinary incontinence, irritable bowel syndrome, andgastrointestinal disorders such as gastrointestinal inflammation andulcer or other diseases. Other agents known to cause libido enhancement,analgesia or local anesthesia may be combined with compounds of thepresent invention.

The compositions may be prepared by methodology well known in thepharmaceutical art. The aminocyclohexyl ether compounds of the presentinvention may be in the form of a solvate in a pharmaceuticallyacceptable solvent such as water or physiological saline. Alternatively,the compounds may be in the form of the free base or in the form of apharmaceutically acceptable salt such as the hydrochloride, sulfate,phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate,maleate, lactate, mandelate, salicylate, succinate and other salts knownin the art. The appropriate salt would be chosen to enhancebioavailability or stability of the compound for the appropriate mode ofemployment (e.g., oral or parenteral routes of administration).

A composition intended to be administered by injection can be preparedby combining the aminocyclohexyl ether compound of the present inventionwith water, and preferably buffering agents, so as to form a solution.The water is preferably sterile pyrogen-free water. A surfactant may beadded to facilitate the formation of a homogeneous solution orsuspension. Surfactants are compounds that non-covalently interact withthe aminocyclohexyl ether compound so as to facilitate dissolution orhomogeneous suspension of the aminocyclohexyl ether compound in theaqueous delivery system. Surfactants are desirably present in aqueouscompositions of the invention because the aminocyclohexyl ethercompounds according to the present invention may be hydrophobic. Othercarriers for injection include, without limitation, sterileperoxide-free ethyl oleate, dehydrated alcohols, propylene glycol, aswell as mixtures thereof.

Suitable pharmaceutical adjuvants for the injecting solutions includestabilizing agents, solubilizing agents, buffers, and viscosityregulators. Examples of these adjuvants include ethanol,ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citratebuffers, and high molecular weight polyethylene oxide viscosityregulators. These pharmaceutical formulations may be injectedintramuscularly, epidurally, intraperitoneally, or intravenously.

As used herein, “treating arrhythmia” refers to therapy for arrhythmia.An effective amount of a composition of the present invention is used totreat arrhythmia in a warm-blooded animal, such as a human. Methods ofadministering effective amounts of antiarrhythmic agents are well knownin the art and include the administration of an oral or parenteraldosage form. Such dosage forms include, but are not limited to,parenteral dosage form. Such dosage forms include, but are not limitedto, parenteral solutions, tablets, capsules, sustained release implants,and transdermal delivery systems. Generally, oral or intravenousadministration is preferred for some treatments. The dosage amount andfrequency are selected to create an effective level of the agent withoutharmful effects. It will generally range from a dosage of from about0.01 to about 100 mg/kg/day, and typically from about 0.1 to 10 mg/kgwhere administered orally or intravenously for antiarrhythmic effect orother therapeutic application.

Administration of compositions of the present invention may be carriedout in combination with the administration of other agents. For example,it may be desired to administer an opioid antagonist, such as naloxone,if a compound exhibits opioid activity where such activity may not bedesired. The naloxone may antagonize opioid activity of the administeredcompound without adverse interference with the antiarrhythmic activity.As another example, an aminocyclohexyl ether compound of the inventionmay be co-administered with epinephrine in order to induce localanesthesia.

Other Compositions

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the above formulae.The kit also includes instructions for the use of the pharmaceuticalcomposition for modulating the activity of ion channels, for thetreatment of arrhythmia or for the production of analgesia and/or localanesthesia, and for the other utilities disclosed herein. Preferably, acommercial package will contain one or more unit doses of thepharmaceutical composition. For example, such a unit dose may be anamount sufficient for the preparation of an intravenous injection. Itwill be evident to those of ordinary skill in the art that compoundswhich are light and/or air sensitive may require special packagingand/or formulation. For example, packaging may be used which is opaqueto light, and/or sealed from contact with ambient air, and/or formulatedwith suitable coatings or excipients.

Pharmacological Embodiments

In other embodiments, the present invention provides one or morecompounds of the present invention such as those according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof; or a composition or medicament that includes said compound ormixture comprising compounds as described above, for use in methods formodulating ion channel activity in a warm-blooded animal or formodulating ion channel activity in vitro. In one version of thisembodiment, the warm-blooded animal in which the ion channel activity ismodulated is a mammal; in one version, the warm-blooded animal is ahuman; in one version, the warm-blooded animal is a farm animal.

In other embodiments, the present invention provides one or morecompounds, selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above, for, use in methods for modulating ionchannel activity in a warm-blooded animal or for modulating ion channelactivity in vitro.

In one version of this embodiment, the warm-blooded animal in which theion channel activity is modulated is a mammal; in one version, thewarm-blooded animal is a human; in one version, the warm-blooded animalis a farm animal.

As disclosed within the present invention, a variety of cardiacpathological conditions may be treated and/or prevented by the use ofone or more compounds of the present invention such as those accordingto formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove. These compounds of the present invention are ion channelmodulating compounds that either singly or together with one or moreadditional compounds are able to selectively modulate certain ioniccurrents. The ion currents referred to herein are generally cardiaccurrents and more specifically, are the sodium currents and earlyrepolarising currents.

Early repolarising currents correspond to those cardiac ionic currentswhich activate rapidly after depolarization of membrane voltage andwhich effect repolarisation of the cell. Many of these currents arepotassium currents and may include, but are not limited to, thetransient outward current I_(to1) such as Kv4.2 and Kv4.3), and theultrarapid delayed rectifier current (I_(Kur)) such as Kv1.5, Kv1.4 andKv2.1). The ultrarapid delayed rectifier current (I_(Kur)) has also beendescribed as I_(sus). A second calcium dependent transient outwardcurrent (I_(to2)) has also been described.

The pathological conditions that may be treated and/or prevented by thepresent invention may include, but are not limited to, variouscardiovascular diseases.

The cardiac pathological conditions that may be treated and/or preventedby the present invention may include, but are not limited to,arrhythmias such as the various types of atrial and ventriculararrhythmias, e.g., atrial fibrillation, atrial flutter, ventricularfibrillation, ventricular flutter.

In one embodiment, the present invention provides ion channel modulatingcompounds that can be used to selectively inhibit cardiac earlyrepolarising currents and cardiac sodium currents.

In another embodiment, the present invention provides ion channelmodulating compounds that can be used to selectively inhibit cardiacearly repolarising currents and cardiac sodium currents under conditionswhere an “arrhythmogenic substrate” is present in the heart. An“arrhythmogenic substrate” is characterized by a reduction in cardiacaction potential duration and/or changes in action potential morphology,premature action potentials, high heart rates and may also includeincreased variability in the time between action potentials and anincrease in cardiac milieu acidity due to ischaemia or inflammation.Changes such as these are observed during conditions of myocardialischaemia or inflammation and those conditions that precede the onset ofarrhythmias such as atrial fibrillation.

In other embodiments, the present invention provides a method formodulating ion channel activity in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof, an effectiveamount of one or more compounds of the present invention such as thoseaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove.

In other embodiments, the present invention provides a method formodulating ion channel activity in an in vitro setting comprisingadministering in vitro an effective amount of one or more compounds ofthe present invention such as those according to formula (IA), (IB),(IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt,ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture,geometric isomer, crystalline or amorphous form, metabolite, metabolicprecursor or prodrug thereof, including isolated enantiomeric,diastereomeric and geometric isomers thereof, and mixtures thereof; or acomposition or medicament that includes said compound or mixturecomprising compounds as described above.

In other embodiments, the present invention provides a method forblocking/inhibiting the activity/conductance of ion channel in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof, an effective amount of one or more compounds of thepresent invention such as those according to formula (IA), (IB), (IC),(ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method forblocking/inhibiting the activity/conductance of ion channel in an invitro setting comprising administering in vitro an effective amount ofone or more compounds of the present invention such as those accordingto formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove.

In other embodiments, the present invention provides a method formodulating potassium ion channel activity in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method formodulating voltage-gated potassium ion channel activity in awarm-blooded animal comprising administering to a warm-blooded animal inneed thereof, an effective amount of one or more compounds of thepresent invention such as those according to formula (IA), (IB), (IC),(ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester,amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method formodulating cardiac sodium currents activity in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method formodulating cardiac early repolarising currents and cardiac sodiumcurrents ion channel activity in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof, an effectiveamount of one or more compounds of the present invention such as thoseaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove.

In other embodiments, the present invention provides a method forblocking/inhibiting cardiac early repolarising currents and cardiacsodium currents ion channel activity in a warm-blooded animal comprisingadministering to a warm-blooded animal in need thereof, an effectiveamount of one or more compounds of the present invention such as thoseaccording to formula (IA), (IB), (IC), (ID), or (IE), or a solvate,pharmaceutically acceptable salt, ester, amide, complex, chelate,stereoisomer, stereoisomeric mixture, geometric isomer, crystalline oramorphous form, metabolite, metabolic precursor or prodrug thereof,including isolated enantiomeric, diastereomeric and geometric isomersthereof, and mixtures thereof; or a composition or medicament thatincludes said compound or mixture comprising compounds as describedabove.

In other embodiments, the present invention provides a method forblocking/inhibiting the cardiac ion channels responsible for cardiacearly repolarising currents and cardiac sodium currents ion channelactivity in a warm-blooded animal comprising administering to awarm-blooded animal in need thereof, an effective amount of one or morecompounds of the present invention such as those according to formula(IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceuticallyacceptable salt, ester, amide, complex, chelate, stereoisomer,stereoisomeric mixture, geometric isomer, crystalline or amorphous form,metabolite, metabolic precursor or prodrug thereof, including isolatedenantiomeric, diastereomeric and geometric isomers thereof, and mixturesthereof; or a composition or medicament that includes said compound ormixture comprising compounds as described above.

In other embodiments, the present invention provides a method forblocking/inhibiting cardiac early repolarising currents and cardiacsodium currents ion channel activity in a warm-blooded animal underconditions where an arrhythmogenic substrate is present in the heart ofsaid warm-blooded animal comprising administering to a warm-bloodedanimal in need thereof, an effective amount of one or more compounds ofthe present invention such as those according to formula (IA), (IB),(IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt,ester, amide, complex, chelate, stereoisomer; stereoisomeric mixture,geometric isomer, crystalline or amorphous form, metabolite, metabolicprecursor or prodrug thereof, including isolated enantiomeric,diastereomeric and geometric isomers thereof, and mixtures thereof; or acomposition or medicament that includes said compound or mixturecomprising compounds as described above.

In other embodiments, the present invention provides a method forblocking/inhibiting the cardiac ion channels responsible for cardiacearly repolarising currents and cardiac sodium currents ion channelactivity in a warm-blooded animal under conditions where anarrhythmogenic substrate is present in the heart of said warm-bloodedanimal comprising administering to a warm-blooded animal in needthereof, an effective amount of one or more compounds of the presentinvention such as those according to formula (IA), (IB), (IC), (ID), or(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the cardiac early repolarising currents referredto in the present invention comprise ionic currents which activaterapidly after depolarisation of membrane voltage and which effectrepolarisation of the cell.

In other embodiments, the cardiac early repolarising currents referredto in the present invention comprise the cardiac transient outwardpotassium current (I_(to)) and/or the ultrarapid delayed rectifiercurrent (I_(Kur)).

In other embodiments, the cardiac transient outward potassium current(I_(to)) and/or the ultrarapid delayed rectifier current (I_(Kur))referred to in the present invention comprise at least one of the Kv4.2,Kv4.3, Kv2.1, Kv1.4 and Kv1.5 currents.

In other embodiments, the present invention provides a method fortreating and/or preventing arrhythmia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In another embodiments, the present invention provides a method fortreating and/or preventing atrial arrhythmia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method fortreating and/or preventing ventricular arrhythmia in a warm-bloodedanimal comprising administering to a warm-blooded animal in needthereof, an effective amount of one or more compounds of the presentinvention such as those according to formula (IA), (IB), (IC), (ID), or(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In another embodiments, the present invention provides a method fortreating and/or preventing atrial fibrillation in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method fortreating and/or preventing ventricular fibrillation in a warm-bloodedanimal comprising administering to a warm-blooded animal in needthereof, an effective amount of one or more compounds of the presentinvention such as those according to formula (IA), (IB), (IC), (ID), or(IE), or a solvate, pharmaceutically acceptable salt, ester, amide,complex, chelate, stereoisomer, stereoisomeric mixture, geometricisomer, crystalline or amorphous form, metabolite, metabolic precursoror prodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In another embodiments, the present invention provides a method fortreating and/or preventing atrial flutter in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In other embodiments, the present invention provides a method fortreating and/or preventing ventricular flutter in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those according to formula (IA), (IB), (IC), (ID), or (IE), or asolvate, pharmaceutically acceptable salt, ester, amide, complex,chelate, stereoisomer, stereoisomeric mixture, geometric isomer,crystalline or amorphous form, metabolite, metabolic precursor orprodrug thereof, including isolated enantiomeric, diastereomeric andgeometric isomers thereof, and mixtures thereof; or a composition ormedicament that includes said compound or mixture comprising compoundsas described above.

In another embodiments, the present invention provides a method fortreating and/or preventing arrhythmia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In another embodiments, the present invention provides a method fortreating and/or preventing atrial arrhythmia in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In another embodiments, the present invention provides a method fortreating and/or preventing ventricular arrhythmia in a warm-bloodedanimal comprising administering to a warm-blooded animal in needthereof, an effective amount of one or more compounds of the presentinvention such as those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In another embodiments, the present invention provides a method fortreating and/or preventing atrial fibrillation in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In another embodiments, the present invention provides a method fortreating and/or preventing ventricular fibrillation in a warm-bloodedanimal comprising administering to a warm-blooded animal in needthereof, an effective amount of one or more compounds of the presentinvention such as those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In another embodiments, the present invention provides a method fortreating and/or preventing atrial flutter in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

In another embodiments, the present invention provides a method fortreating and/or preventing ventricular flutter in a warm-blooded animalcomprising administering to a warm-blooded animal in need thereof, aneffective amount of one or more compounds of the present invention suchas those selected from the group consisting of:

(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof;

(1R,2S)/(1S,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanefree base or any salt thereof, or any solvate thereof; or a compositionor medicament that includes said compound or mixture comprisingcompounds as described above.

As noted above, the present invention provides for utilizing thecompounds described above in in vitro and in vivo methods. In oneembodiment, ion channels, such as cardiac potassium channels, areblocked in vitro or in vivo.

Ion channels are ubiquitous membrane proteins in the cells ofwarm-blooded animals such as mammals. Their critical physiological rolesinclude control of the electrical potential across the membrane,mediation of ionic and fluid balance, facilitation of neuromuscular andneuronal transmission, rapid transmembrane signal transduction, andregulation of secretion and contractility.

Accordingly, compounds that are capable of modulating the activity orfunction of the appropriate ion channels will be useful in treatingand/or preventing a variety of diseases or disorders caused by defectiveor inadequate function of the ion channels. The compounds of theinvention are found to have significant activity in modulating variousion channel activity both in vivo and in vitro.

In one embodiment, the present invention provides a compound of thepresent invention or a composition containing said compound, for use inmethods for either modulating ion channel activity in a warm-bloodedanimal or for modulating ion channel activity in vitro. Some of the ionchannels to which the compounds, compositions and methods of the presentinvention have modulating effect are various potassium and sodiumchannels. These potassium and sodium ion channels may bevoltage-activated (also known as voltage-gated) or ligand-activated(also known as ligand-gated), and may be present in cardiac and/orneuronal systems.

In one embodiment, the invention provides a compound of the presentinvention such as those according to formula (IA), (IB), (IC), (ID) or(IE), or composition containing said compound, for use in methods foreither modulating activity of ion channel(s) in a warm-blooded animal orfor modulating activity of ion channel(s) in vitro, wherein said ionchannel(s) correspond to some of the cardiac and/or neuronal ionchannels that are responsible for one or more early repolarisingcurrents comprising those which activate rapidly after membranedepolarisation and which effect repolarisation of the cells.

In another embodiment, of the present invention, the above-mentionedearly repolarising currents comprise the transient outward potassiumcurrent (I_(to) for cardiac or I_(A) for neuronal) and/or the ultrarapiddelayed rectifier current (I_(Kur)); and include at least one of theKv4.2, Kv4.3, Kv2.1, Kv1.3, Kv1.4 and Kv1.5 currents.

In another embodiment, the present invention provides a compound of thepresent invention such as those according to formula (IA), (IB), (IC),(ID) or (IE), or composition containing said compound, for use inmethods for either modulating activity of ion channel(s) in awarm-blooded animal or for modulating activity of ion channel(s) invitro, wherein said ion channel(s) correspond to either the cardiac orneuronal ion channel(s) that are responsible for Kv1.5 current.

In yet another embodiment, the present invention provides a compound ofthe present invention such as those according to formula (IA), (IB),(IC), (ID) or (IE), or composition containing said compound, for use inmethods for either modulating activity of ion channel(s) in awarm-blooded animal or for modulating activity of ion channel(s) invitro, wherein said ion channel(s) correspond to the potassium channelthat are responsible for Kv4.2 current.

Furthermore, the voltage-activated sodium ion channels comprise theNa_(v)1, Na_(v)2 or Na_(v)3 series and may be present in cardiac,neuronal, skeletal muscle, central nervous and/or peripheral nervoussystems (e.g., hH1Na).

For cardiac sodium channels, in studies on ion channels in isolatedhuman atrial myocytes, compounds of the present invention have beenshown to produce frequency-dependent blockade of cardiac sodiumchannels. In these studies enhanced blockade of cardiac sodium channelswas observed at faster rates of stimulation with sodium block increasingseveral-fold during rapid stimulation rates. These protocols have beendesigned to mimic the short recovery intervals during fibrillation.

As noted earlier, modulating the activity of an ion channel as usedabove may imply but does not limit to blocking or inhibiting theconductance of the current through the ion channel.

Thus, the present invention provides for methods of treating a diseaseor condition in a warm-blooded animal suffering from or having thedisease or condition, and/or preventing a disease or condition fromarising in a warm-blooded animal, wherein a therapeutically effectiveamount of a compound of the present invention, or a compositioncontaining a compound of the present invention is administered to awarm-blooded animal in need thereof. Some of the diseases and conditionsto which the compounds, compositions and methods of the presentinvention may be applied are as follows: arrhythmia includingatrial/supraventricular arrhythmia and ventricular arrhythmia, atrialfibrillation, ventricular fibrillation, atrial flutter, ventricularflutter, diseases of the central nervous system, convulsion,cardiovascular diseases (e.g., diseases caused by elevated bloodcholesterol or triglyceride levels), cerebral or myocardial ischemias,hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases,diabetes mellitus, myopathies, Becker's myotonia; myasthenia gravis,paramyotonia congentia, malignant hyperthermia, hyperkalemic periodicparalysis, Thomsen's myotonia, autoimmune disorders, graft rejection inorgan transplantation or bone marrow transplantation, heart failure,hypotension, Alzheimer's disease, dementia and other mental disorder,alopecia, sexual dysfunction, impotence, demyelinating diseases,multiple sclerosis, amyotrophic lateral sclerosis, epileptic spasms,depression, anxiety, schizophrenia, Parkinson's disease, respiratorydisorders, cystic fibrosis, asthma, cough, inflammation, arthritis,allergies, urinary incontinence, irritable bowel syndrome, andgastrointestinal disorders such as gastrointestinal inflammation andulcer.

Furthermore, the present invention provides a method for producinganalgesia or local anesthesia in a warm-blooded animal which includesadministering to a warm-blooded animal in need thereof an effectiveamount of a compound of the present invention or a pharmaceuticalcomposition containing said compound. These methods may be used torelieve or forestall the sensation of pain in a warm-blooded animal.

The invention further provides a method for enhancing libido in awarm-blooded animal which includes administering to a warm-bloodedanimal in need thereof an effective amount of a compound of the presentinvention or a pharmaceutical composition containing said compound.These compositions and methods may be used, for example, to treat asexual dysfunction, e.g., impotence in males, and/or to enhance thesexual desire of a patient without a sexual dysfunction. As anotherexample, the therapeutically effective amount may be administered to abull (or other breeding stock), to promote increased semen ejaculation,where the ejaculated semen is collected and stored for use as it isneeded to impregnate female cows in promotion of a breeding program.

Furthermore, the present invention provides a method in an in vitrosetting, wherein a preparation that contains ion channels is contactedwith an effective amount of an aminocyclohexyl ether compound of theinvention. Suitable preparations containing cardiac sodium channelsand/or cardiac, potassium channels include cells isolated from cardiactissue as well as cultured cell lines. The step of contacting includes,for example, incubation of ion channels with a compound under conditionsand for a time sufficient to permit modulation of the activity of thechannels by the compound.

Administration of compositions of the present invention may be carriedout in combination with the administration of other agents. For example,it may be desired to administer an opioid antagonist, such as naloxone,if a compound exhibits opioid activity where such activity may not bedesired. The naloxone may antagonize opioid activity of the administeredcompound without adverse interference with the antiarrhythmic activity.As another example, an aminocyclohexyl ether compound of the inventionmay be co-administered with epinephrine in order to induce localanesthesia.

In order to assess whether a compound has a desired pharmacologicalactivity with the present invention, it may be subjected to a series oftests. The precise test to employ will depend on the physiologicalresponse of interest. The published literature contains numerousprotocols for testing the efficacy of a potential therapeutic agent, andthese protocols may be employed with the present compounds andcompositions.

For example, in connection with treatment or prevention of arrhythmia, aseries of four tests may be conducted. In the first of these tests, acompound of the present invention is given as increasing (doubling witheach dose) intravenous infusion every 5 minutes to a conscious rat. Theeffects of the compound on blood pressure, heart rate and the ECG aremeasured continuously. Increasing doses are given until a severe adverseevent occurs. The drug related adverse event is identified as being ofrespiratory, central nervous system or cardiovascular system origin.This test gives an indication as to whether the compound is modulatingthe activity of sodium channels and/or potassium channels, and inaddition gives information about acute toxicity. The indices of sodiumchannel blockade are increasing P—R interval and QRS widening of theECG. Potassium channel blockade results in Q-T interval prolongation ofthe ECG.

A second test involves administration of a compound as an infusion topentobarbital anesthetized rats in which the left ventricle is subjectedto electrical square wave stimulation performed according to a presetprotocol described in further detail below. This protocol includes thedetermination of thresholds for induction of extrasystoles andventricular fibrillation. In addition, effects on electricalrefractoriness are assessed by a single extra beat technique. Inaddition effects on blood pressure, heart rate and the ECG are recorded.In this test, sodium channel blockers produce the ECG changes expectedfrom the first test. In addition, sodium channel blockers also raise thethresholds for induction of extrasystoles and ventricular fibrillation.Potassium channel blockade is revealed by increasing refractoriness andwidening of the Q-T intervals of the ECG.

A third test involves exposing isolated rat hearts to increasingconcentrations of a compound. Ventricular pressures, heart rate,conduction velocity and ECG are recorded in the isolated heart in thepresence of varying concentrations of the compound. The test providesevidence for direct toxic effects on the myocardium. Additionally,selectivity, potency and efficacy of action of a compound can beascertained under conditions simulating ischemia. Concentrations foundto be effective in this test are expected to be efficacious in theelectrophysiological studies.

A fourth test is estimation of the antiarrhythmic activity of a compoundagainst the arrhythmias induced by coronary artery occlusion inanaesthetized rats. It is expected that a good antiarrhythmic compoundwill have antiarrhythmic activity at doses which have minimal effects oneither the ECG, blood pressure or heart rate under normal conditions.

All of the foregoing tests are performed using rat tissue. In order toensure that a compound is not having effects which are only specific torat tissue, further experiments are performed in dogs and primates. Inorder to assess possible sodium channel and potassium channel blockingaction in vivo in dogs, a compound is tested for effects on the ECG,ventricular epicardial conduction velocity and responses to electricalstimulation. An anesthetized dog is subjected to an open chest procedureto expose the left ventricular epicardium. After the pericardium isremoved from the heart a recording/stimulation electrode is sewn ontothe epicardial surface of the left ventricle. Using this array, andsuitable stimulation protocols, conduction velocity across theepicardium as well as responsiveness to electrical stimulation can beassessed. This information coupled with measurements of the ECG allowsone to assess whether sodium and/or potassium channel blockade occurs.As in the first test in rats, a compound is given as a series ofincreasing bolus doses. At the same time possible toxic effects of acompound on the dog's cardiovascular system is assessed.

The effects of a compound on the ECG and responses to electricalstimulation are also assessed in intact, anesthetized monkeys (Macacafascicularis). In this preparation, a blood pressure cannula and ECGelectrodes are suitably placed in an anesthetized monkey. In addition, astimulating electrode is placed onto the right atria and/or ventricle,together with monophasic action potential electrode. As in the testsdescribed above, ECG and electrical stimulation response to a compoundreveal the possible presence of sodium and/or potassium channelblockade. The monophasic action potential also reveals whether acompound widens the action potential, an action expected of a potassiumchannel blocker.

As another example, in connection with the mitigation or prevention ofthe sensation of pain, the following test may be performed. To determinethe effects of a compound of the present invention on an animal'sresponse to a sharp pain sensation, the effects of a slight prick from a7.5 g weighted syringe fitted with a 23G needle as applied to the shavedback of a guinea pig (Cavia porcellus) is assessed followingsubcutaneous administration of sufficient (50 μl, 10 mg/ml) solution insaline to raise a visible bleb on the skin. Each test is performed onthe central area of the bleb and also on its periphery to check fordiffusion of the test solution from the point of administration. If thetest animal produces a flinch in response to the stimulus, thisdemonstrates the absence of blockade of pain sensation. Testing may becarried out at intervals for up to 8 hours or more post-administration.The sites of bleb formation are examined after 24 hours to check forskin abnormalities consequent to local administration of test substancesor of the vehicle used for preparation of the test solutions.

The following examples are offered by way of illustration and not by wayof limitation. In the Examples, and unless otherwise specified, startingmaterials were obtained from well-known commercial supply houses, e.g.,Aldrich Chemical Company (Milwaukee, Wis.), and were of standard gradeand purity. “Ether” and “ethyl ether” each refers to diethyl ether; “h.”refers to hours; “min.” refers to minutes; “GC” refers to gaschromatography; “v/v” refers to volume per volume; and ratios are weightratios unless otherwise indicated.

EXAMPLE 1(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride (Compound 1)

The reaction scheme for the preparation of compound 1 described hereinis illustrated in FIG. 1.

Preparation of Intermediates N-tert-Butoxycarbonyl-3R-pyrrolidinol (1R)

To a cold (0° C.) stirred solution of (R)-3-pyrrolidinol (20.6 g, 236mmol; Omega cat. # HP-2113) in anhydrous THF (800 mL) was added dropwisea solution of di-tert-butyldicarbonate (56.7 g, 260 mmol, Aldrich cat.#20, 524-9) in THF (200 mL), and the resultant solution was stirred atroom temperature for 18 h. Concentration in vacuo of the reactionmixture and short-path distillation in vacuo of the clear yellow residuegave 1R (42 g, 95% yield) as clear and colourless oil, whichcrystallized on standing.

Characterization: R_(f) 0.58 (CHCl₃-MeOH, 4:1, v/v), NMR (200 MHz,CDCl₃) δ 4.4 (br s, 1H), 3.5-3.2 (m, 4H), 2.5 (br s, 1H), 2.0-1.9 (m,2H), 1.4 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 154.7, 79.3, 70.6, 69.8,54.1, 53.9, 43.9, 43.4, 33.8, 33.3, 28.4; IR (film) 3411, 1678 cm⁻¹;EIMS m/z (relative intensity) 187 (M⁺, 8), 169 (M-H₂O, 0.5), 132 (25);114 (39), 87 (13), 57 (100); FIRMS m/z calcd for C₉H₁₇NO₃ (M⁺)187.12081. found 187.12084.

N-tert-Butoxycarbonyl-3R-benzyloxypyrrolidine (2R)

A suspension of sodium hydride (8.08 g, 269 mmol, 80%, Aldrich cat. #25,399-5) in anhydrous THF (100 mL) was stirred, allowed to settle and thesupernatant was discarded. The grey residue was washed with THF (2×50mL) and then re-suspended in THF (700 mL). To the cold (0° C.), stirredsuspension of sodium hydride was added dropwise a solution of 1R (41.7g, 223 mmol) in THF (200 mL) and the resultant mixture was refluxed for1 h. After the reaction mixture had cooled to room temperature, benzylbromide (26.5 mL, 223 mmol) and tetrabutylammonium iodide (8.20 g, 22.3mmol, Aldrich cat. #14,077-5) were successively added. The mixture wasstirred at room temperature for 18 h and then concentrated under reducedpressure. To the residue was added brine (300 mL) and water (50 mL), andthe pH of the resultant mixture was adjusted to neutrality with 1M aqHCl. This mixture was extracted with hexane (100 mL), and the hexaneextract was dried (MgSO₄ anhydr) and concentrated under reduced pressureto give 64.3 g (>98% yield) of a yellow oil, which was shown by GCanalysis to consist almost exclusively of the desired product. A smallamount of the oil was subjected to flash column chromatography on silicagel eluted with hexane-ethyl acetate (3:1) to give 2R as a colourlessoil, which crystallized on standing.

Characterization of 2R: R_(f) 0.58 (CHCl₃-MeOH, 4:1, v/v), ¹H NMR (400MHz, CDCl₃) δ 7.35-7.25 (m, 5H), 4.58-4.47 (m, 2H), 4.12 (br s, 1H),3.55-3.40 (m, 4H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.48 (s, 9H);¹³C NMR (75 MHz, CDCl₃) δ 154.5, 138.0, 128.3, 127.6, 79.1, 77.7, 76.8,70.8, 51.4, 50.7, 44.0, 43.6, 31.4, 30.4, 28.4; IR (film) 2975, 1691,1410 cm⁻¹; HRMS m/z calcd for C₁₆H₂₃NO₃ (M) 277.16779. found 277.16790.

3R-Benzyloxypyrrolidine (3R)

A mixture of trifluoroacetic acid (50 mL, Aldrich cat. #T6, 220-0) and2R (20 g, 72 mmol) was stirred at room temperature for 1 h and thenconcentrated under reduced pressure. The residue was taken up in water(250 mL) and the resultant acidic aqueous solution was extracted withEt₂O (2×150 mL). To the acidic aqueous layer was carefully added inportions solid NaHCO₃ until saturation. The basic aqueous solution wasthen extracted with CH₂Cl₂ (2×150 mL) and the combined organic extractswere dried (Na₂SO₄ anhydr). Evaporation of the solvent in vacuo yielded8.0 g of 3R (62% yield).

Characterization of 3R: R_(f) 0.24 (CHCl₃-MeOH, 9:1, v/v), NMR (400 MHz,CDCl₃) δ 7.40-7.17 (m, 5H), 4.43 (s, 2H), 4.09-4.03 (m, 1H), 3.10-2.98(m, 2H), 2.85-2.70 (m, 2H), 2.46 (s, 1H), 1.90-1.78 (m, 2H); IR (film)3400, 1452, 1100, 1068 cm⁻¹.

(1R,2R)/(1S,2S)-1-[(3R)-benzyloxypyrrolidinyl]cyclohexan-2-ol (4R)

A mixture of cyclohexene oxide (12.5 mL, 120.9 mmol, Aldrich cat. #C10,250-4), 3R (14.3 g, 80.6 mmol) and water (6 mL) was heated at 80° C. for9.5 h, after which GC analysis revealed complete consumption of 3R. Thereaction mixture was allowed to cool to room temperature and dilutedwith water (140 mL). By the addition of 1M aq HCl (55 mL), the pH wasadjusted to 4.6 and the mixture was extracted with Et₂O (2×200 mL).After the aqueous layer was adjusted to pH 12.5 by the addition of 40%aq NaOH (NaCl may be added to effect separation into 2 clear layers), itwas extracted with Et₂O (1×400 mL, 1×200 mL). The combined Et₂O extracts(from basic aqueous layer) were dried (Na₂SO₄ anhydr), and concentratedunder reduced pressure and then in vacuo at 55° C. with stirring, togive 4R as an orange oil (15.9 g, 72%) of 96% purity (GC).

Characterization of 4R: R_(f) 0.24 (EtOAc-iPrNH₂, 98:2, v/v); ¹H NMR(200 MHz, CDCl₃) δ 7:4-7.2 (m, 5H), 4.5 (s, 2H), 4.2-4.0 (m, 1H), 3.9(br s, 1H), 3.4-3.2 (m, 1H), 3.0-2.5 (m, 4H), 2.4 (t, J 10 Hz, 1H),2.2-1.9 (m, 2H), 1.9-1.6 (m, 4H), 1.3-1.1 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ 138.30, 128.35, 127.61, 127.55, 77.98, 77.71, 71.07, 71.01,70.52, 70.45, 64.96, 64.89, 54.16, 52.74, 46.83, 45.43, 33.24, 31.53,31.34, 25.20, 24.13, 21.40, 21.33; IR (film) 3450 (broad) cm⁻¹.

(1R,2R)/(1S,2S)-2-[(3R)-Benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane(5R)

(a) To a cold (0° C.), stirred solution of 4R (32.7 g, 88% purity by GCanalysis, 104 mmol) and Et₃N (13.8 g, 135 mmol, Aldrich cat. #13, 206-3)in CH₂Cl₂ (210 mL) was added dropwise methanesulfonyl chloride (15.8 g,135 mmol, Aldrich cat. #M880-0). The reaction mixture was stirred at 0°C. for 30 min. and then at room temperature for 2 hours 15 min. Thereaction mixture was then washed with a 1:1 mixture of H₂O-saturated aqNaHCO₃ (200 mL). The aqueous layer was extracted with CH₂Cl₂ (1×200 mL,2×150 mL) and the organic extracts were combined and dried over sodiumsulfate. Concentration of the organic layer in vacuo yielded the crudemesylate as a viscous oil, which was stirred under high vacuum for 3 hto removal residual traces of volatile material, and then used in thenext step without further purification.

(b) To a suspension of NaH (3.75 g, 80% dispersion in mineral oil, 125mmol, Aldrich cat. #25, 399-5) in anhydrous ethylene glycol dimethylether (350 mL) was added a solution of 3,4-dimethoxyphenethyl alcohol(23.2 g, 125 mmol, Aldrich cat. #19, 765-3) in ethylene glycol dimethylether (100 mL). The resultant mixture was then stirred at roomtemperature for 2 h to complete formation of the sodium alkoxide.

A solution of mesylate (see part a above) in anhydrous ethylene glycoldimethyl ether (100 mL) was added quickly to the alkoxide mixture (seepart b above) and the resultant mixture was refluxed under argon for 17h. The reaction mixture was allowed to cool to room temperature and thenquenched with water (200 mL), followed by concentration under reducedpressure. The resultant aqueous solution was diluted with water (400 mL)and its pH was adjusted to pH 0.5 by the addition of 10% aq HCl. Toremove unreacted 3,4-dimethoxyphenethyl alcohol, the acidic aqueouslayer was extracted with Et₂O (2×600 mL). The pH of the aqueous solutionwas then adjusted to pH 6.3 by the addition of 5M aq NaOH and theresultant aqueous layer was extracted with Et₂O (600 mL). To the aqueouslayer was added Et₂O (600 mL), the pH was adjusted to 6.4 and the layerswere separated. This operation was repeated for pH adjustments to 6.5and 6.7. The ether extracts following pH adjustments 6.3-6.7 werecombined, concentrated under reduced pressure to a volume of ˜800 mL,and dried (Na₂SO₄ anhydr). Removal of solvent in vacuo yielded 34.4 g(95% purity by GC analysis) of the title compound as a brown oil.Purification of this material by flash column chromatography on silicagel eluted with a gradient solvent system of hexane-EtOAc (6.6:1→2:1)containing 0.5% v/v i-PrNH₂ gave the diastereomeric mixture 5R as ayellow oil (70% yield) in two fractions: 7.9 g (97% purity by GCanalysis) and 25.5 g (95% purity by GC analysis).

Characterization: R_(f) 0.14 (hexanes-EtOAc, 2:1 containing 0.5%i-PrNH₂); ¹³C NMR (100 MHz, CDCl₃) δ 148.94, 147.59, 138.77, 132.30,128.30, 127.62, 127.42, 120.90, 112.77, 111.55, 79.18, 78.07, 70.93,69.82, 63.93, 57.46, 56.02, 55.90, 49.22, 36.59, 31.37, 28.70, 26.97,23.08, 22.82; EIMS m/z (relative intensity) 440 (M+, 2) 333 (15) 274(67) 165 (40) 91 (100).

Resolution of (1S,2S)- and(1R,2R)-2-[(3R)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanes(5RRR and 5SSR)

The diastereomeric mixture 5R was separated using a Prochrom 110 HPLCequipped with a column body of 110 mm internal diameter, a bed length of850 mm, and a maximum bed length of 400 mm (packed column). The columnwas packed with Kromasil silica (10 micron, 100 angstrom, normal phase).5RRR was isolated with a diastereoselectivity of 99.5% and chemicalpurity of 97%.

Preparation of Compound (1),(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride

To a 500 mL Erlenmeyer flask equipped with a 24/40 joint at 22° C. andcharged with a stirred solution of 5RRR (12.7 mmol) in isopropyl alcohol(70 mL, HPLC grade from EM science, cat. No. PX1838-1) was addeddropwise a solution of hydrochloric acid (5 mL, 37%, Aldrich #25,814-8).After the solution was stirred for 10 minutes, Pd—C catalyst (1.5 g,10%, Adrich #20,569-9) was added and the reaction vessel was equippedwith a gas inlet adapter (24/40 joint, Kontes cat. no. KT185030-2440)connected to a water aspirator. The reaction flask was evacuated bywater aspiration for 1 min and then charged with H₂ via a balloonattached to the gas inlet. After the reaction mixture was stirredvigorously for 1 h at 22° C. under a positive pressure of H₂, TLC and GCanalysis indicated total consumption of substrate and clean conversioninto the desired product. The reaction mixture was filtered through aCelite 545® (Fisher)-packed column (45 mm in diameter and 35 mm inheight, pre-wet with methanol under suction to rid air pockets and toensure efficient charcoal trapping during filtration) and the Pd—Ccatalyst was well rinsed with methanol (3×40 mL). The acidic methanolicsolution was concentrated under reduced pressure azeotropically withbenzene or toluene to give a residue which was stirred vigorously inethyl acetate over 1-2 days to facilitate formation of a solid orcrystals.

Characterization: m.p. 144-150° C.; R_(f) 0.37 (AcOEt/isoPrNH2, 95:5);IR 1514, 1263, 1111 cm⁻¹; MS (ES) m/z 350.5; ¹³C NMR (75 MHz, CDCl₃) δ148.84, 147.57, 131.10, 120.54, 112.14, 111.26, 69.41, 68.81, 67.51,66.32, 59.48, 55.88, 52.35, 35.80, 32.32, 30.06, 28.05, 24.23, 22.95;Calcd for C₂₀H₃₁NO₄.HCl: C, 62.24%; H, 8.36%; N, 3.63%. Found: C,62.00%; H, 8.42%; N, 3.57%; [α]_(D)−46.7° (c 1.52, CH₃OH); [α]_(D)−39.6°(c 1.00, CHCl₃)

Preparation of Single Crystals of Compound 1 for X-Ray Crystallography

Compound 1 (200 mg) was dissolved in warm EtOH (3 mL) and then thesolution was allowed to evaporate slowly at room temperature for 3 days.Crystals had formed and further evaporation of the remaining solvent (˜1mL) for another 2 days provided suitable crystals for X-Ray diffractionmeasurements. The sample was stored under Argon.

X-Ray Structure Determination of Compound 1

Experimental

Data Collection

A clear platelet crystal of C₂₀H₃₂NO₄Cl having approximate dimensions of0.25×0.20×0.04 mm was mounted on a glass fiber. All measurements weremade on an ADSC CCD area detector coupled with a Rigaku AFC7diffractometer with graphite monochromated Mo—Kαradiation.

Cell constants and an orientation matrix for data collectioncorresponded to a monoclinic cell with dimensions:

$\begin{matrix}{a = {8.4333(7)Å}} & \; \\{b = {9.4675(9)Å}} & {\beta = {93.125(7)^{O}}} \\{c = {12.581(1)Å}} & \; \\{V = {1003.0(1)Å^{3}}} & \;\end{matrix}$

For Z=2 and F.W.=385.93, the calculated density is 1.28 g/cm³. Based onthe systematic absences of:0k0:k±2na statistical analysis of intensity distribution, and the successfulsolution and refinement of the structure, the space group was determinedto be:P2₁(#4)

The data were collected at a temperature of −100±1° C. to a maximum 2θvalue of 50.2°. Data were collected in 0.50° oscillations with 60.0second exposures. A sweep of data was done using ω oscillations from−18.0 to 23.0° at χ=−90.0°. A second sweep was performed using φoscillations from 0.0 to 190.0° at χ=−90.0°. The crystal-to-detectordistance was 39.68 mm. The detector swing angle was −5.50°.

Data Reduction

Of the 7703 reflections which were collected, 3390 were unique(R_(int)=0.053, Friedels not merged); equivalent reflections weremerged. Data were collected and processed using d*TREK¹. Net intensitiesand sigmas were derived as follows:F ²=[Σ(P _(i) −mB _(ave))]·Lp

where P_(i) is the value in counts of the i^(th) pixel

m is the number of pixels in the integration area

B_(ave) is the background average

Lp is the Lorentz and polarization factorB _(ave)=Σ(B _(j))/n

where n is the number of pixels in the background area

B_(j) is the value of the j^(th) pixel in countsσ²(F ² _(hkl))=[(ΣP _(i))+m((Σ(B _(ave) −B_(j))²)/(n−1))]·Lp·errmul+(erradd·F ²)²

where erradd=0.05

errmul=1.40

The linear absorption coefficient, μ, for Mo—Kα radiation is 2.1 cm⁻¹.An empirical absorption correction was applied which resulted intransmission factors ranging from 0.73 to 1.00. The data were correctedfor Lorentz and polarization effects.

Structure Solution and Refinement

The structure was solved by direct methods² and expanded using Fouriertechniques³. The non-hydrogen atoms were refined anisotropically. Thisconfiguration was chosen based on the results of a parallel refinementof both possible configurations, and was further confirmed by therefined Flack parameter. Hydrogen atoms involved in hydrogen-bondingwere refined isotropically, the rest were included in fixed positions.The final cycle of full-matrix least-squares refinement⁴ on F² was basedon 3390 observed reflections and 242 variable parameters and converged(largest parameter shift was 0.00 times its esd) with unweighted andweighted agreement factors of:R1=Σ∥Fo|−|Fc∥/Σ|Fo|=0.057wR2=[Σ(w(Fo ² −Fc ²)²)/Σw(Fo ²)²]^(1/2)=0.082

The standard deviation of an observation of unit weight⁵ was 0.97. Theweighting scheme was based on counting statistics. Plots of Σw(|Fo|−|Fc|)² versus |Fo|, reflection order in data collection, sin θ/λand various classes of indices showed no unusual trends. The maximum andminimum peaks on the final difference Fourier map corresponded to 0.30and −0.32 e⁻/Å³, respectively.

Neutral atom scattering factors were taken from Cromer and Waber⁶.Anomalous dispersion effects were included in Fcalc⁷; the values for Δf′and Δf′ were those of Creagh and McAuley⁸. The values for the massattenuation coefficients are those of Creagh and Hubbell⁹. Allcalculations were performed using the teXsan¹⁰ crystallographic softwarepackage of Molecular Structure Corporation.

REFERENCES

-   (1) d*TREK: Area Detector Software. Version 4.13. Molecular    Structure Corporation. (1996-1998).-   (2) SIR97: Altomare, A., Burla, M. C., Cammalli, G. Cascarano, M.,    Giacovazzo, C., Guagliardi, A, Moliterni, A. G. G., Polidori, G.,    Spagna, A. SIR97: a new tool for crystal structure determination and    refinement. (1990). J. Appl. Cryst., 32, 115-119.-   (3) DIRDIF94: Beurskens, P. T., Admiraal, G., Beurskens, G.,    Bosman, W. P., de Gelder, R., Israel, R. and Smits, J. M. M. (1994).    The DIRDIF-94 program system, Technical Report of the    Crystallography Laboratory, University of Nijmegen, The Netherlands.-   (4) Least Squares function minimized:    Σw(F _(o) ² −F _(c) ²)²-   (5) Standard deviation of an observation of unit weight:    [Σw(F _(o) ² −F _(c) ²)²/(N _(o) −N _(v))]^(1/2)

where:

-   -   N_(o)=number of observations    -   N_(v)=number of variables

-   (6) Cromer, D. T. & Waber, J. T.; “International Tables for X-ray    Crystallography”, Vol. IV, The Kynoch Press, Birmingham, England,    Table 2.2 A (1974).

-   (7) Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781    (1964).

-   (8) Creagh, D. C. & McAuley, W. J.; “International Tables for    Crystallography”, Vol C, (A. J. C. Wilson, ed.), Kluwer Academic    Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).

-   (9) Creagh, D. C. & Hubbell, J. H.; “International Tables for    Crystallography”, Vol C, (A. J. C. Wilson, ed.), Kluwer Academic    Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).

-   (10) teXsan for Windows version 1.06: Crystal Structure Analysis    Package, Molecular Structure Corporation (1997-9).

EXPERIMENTAL DETAILS A. Crystal Data Empirical Formula C₂₀H₃₂NO₄ClFormula Weight 385.93 Crystal Color, Habit clear, platelet CrystalDimensions 0.25 × 0.20 × 0.04 mm Crystal System monoclinic Lattice TypePrimitive Lattice Parameters a = 8.4333(7) Å b = 9.4675(9) Å c =12.581(1) Å β = 93.125(7)° V = 1003.0(1) Å³ Space Group P2₁ (#4) Z value2 D_(calc) 1.278 g/cm³ F₀₀₀ 416.00 μ(MoKα) 2.15 cm⁻¹ B. IntensityMeasurements Detector ADSC Quantum 1 CCD Goniometer Rigaku AFC7Radiation MoKα (λ = 0.71069 Å) graphite monochromated Detector Aperture94 mm × 94 mm Data Images 462 exposures @ 60.0 seconds ω oscillationRange −18.0-23.0° (χ = −90.0) φ oscillation Range 0.0-190.0° (χ = −90.0)Detector Position 39.68 mm Detector Swing Angle −5.50° 2θ_(max) 50.2°No. of Reflections Measured Total: 7703 Unique: 3390 (R_(int) = 0.053,Friedels not merged) Corrections Lorentz-polarizationAbsorption/decay/scaling (trans. factors: 0.7295-1.0000) C. StructureSolution and Refinement Structure Solution Direct Methods (SIR97)Refinement Full-matrix least-squares on F² Function Minimized Σ w (Fo² −Fc²)² Least Squares Weights 1/σ²(Fo²) = 4Fo²/σ²(Fo²) AnomalousDispersion All non-hydrogen atoms No. Observations (I > 3390 0.00σ(I))No. Variables 242 Reflection/Parameter Ratio 14.01 Residuals (refined onF², 0.057; 0.082 all data): R1; wR2 Goodness of Fit Indicator 0.97 MaxShift/Error in Final Cycle 0.00 No. Observations (I > 3.00σ(I)) 2624Residuals (refined on F > 0.033; 0.038 3.00σ(I)): R1; wR2 Maximum peakin Final Diff. Map 0.30 e⁻/Å³ Minimum peak in Final Diff. Map −0.32e⁻/Å³

The results of the X-ray structure determination for compound 1confirmed the absolute configuration and structural assignment as(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride. By inference and spectroscopic analyses, the absoluteconfiguration and structural assignment for compound 2, compound 3,compound 4, compound 5, compound 6 and compound 7 are confirmedaccordingly.

EXAMPLE 2(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride (Compound 2)

5SSR,(1S,2S)-2-[(3R)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanewas prepared and resolved according to Example 1. Compound 2 was thenobtained from 5SSR using the procedure described above in example 1 withrespect to the preparation of Compound 1.

Characterization: Calcd for C₂₀H₃₁NO₄.HCl: C, 62.24; H, 8.36; N, 3.63.Found: C, 62.20; H, 8.46; N, 3.55; [α]_(D)+26.69° (c 13.04 g/L, CHCl₃)

EXAMPLE 3(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 3) Preparation of Intermediates

N-Benzyloxycarbonyl-3-pyrrolidinol (1b). To a cold (−60° C.) solution of1a (20.0 g, 225 mmol) and Et₃N (79 mL, 560 mmol) in CH₂Cl₂ (200 mL) wasadded dropwise a solution of benzyl chloroformate (34 mL, 225 mmol) inCH₂Cl₂ (80 mL). After the addition was completed within 45 min, thereaction mixture (a yellow suspension) was allowed to warm up to roomtemperature and was stirred under argon at room temperature overnight.The reaction mixture was then quenched with 1M HCl aq (350 mL) and theorganic layer was collected. The acidic aqueous layer was extracted withCH₂Cl₂ (2×150 mL) and the combined organic layers were dried.Evaporation in vacuo of the solvent provided 59.6 g of pale yellow oil,which was further pumped under high vacuum for 15 min to yield 58.2 g(17% over theoretical yield) of 1b suitable for the next step withoutany further purification. R_(f) 0.42 (EtOAc-iPrNH₂, 98:2, v/v); NMR (200MHz, CDCl₃) δ 7.40-7.30 (m, 5H), 5.10 (s, 2H), 4.40 (br s, 1H),3.60-3.40 (m, 4H), 2.80 (d, J 15 Hz, 1H), 2.00-1.90 (m, 2H); ¹³C NMR (50MHz, APT, CDCl₃) δ 137.0 (+), 128.5 (−), 127.5 (−), 71.0 (−), 70.0 (−),66.5 (+), 55.0 (+), 54.5 (+), 44.0 (+), 43.5 (+), 34.0 (+), 33.5 (+); IR(film) 3415 (broad), 1678 cm⁻¹.

N-Benzyloxycarbonyl-3-pyrrolidinone (1c). To a chilled (−60° C.)solution of oxalyl chloride (23 mL, 258.6 mmol) in CH₂Cl₂ (400 mL) wasadded dropwise a solution of DMSO (36.7 mL, 517.3 mmol) in CH₂Cl₂ (20mL) at such a rate to keep the temperature below −40° C. The reactionmixture was then stirred at −60° C. for 15 min. Then a solution of 1b(58.2 g, no more than 225 mmol) in CH₂Cl₂ (80 mL) was added dropwise,keeping the reaction mixture temperature below −50° C. The reactionmixture was then stirred at −60° C. for 30 min before adding Et₃N (158.3mL, 1.125 mol). The resulting mixture was allowed to warm up to roomtemperature and then washed with water (600 mL), 1M HCl aq (580 mL) andwater (400 mL). The organic layer was dried and concentrated in vacuo toleave 54.5 g of amber oil, which was further pumped under high vacuumwith stirring at room temperature for 25 min to give 52 g (5.6% overtheoretical yield) of 1c suitable for the next step without any furtherpurification. R_(f) 0.81 (EtOAc-iPrNH₂, 98:2, v/v); ¹H NMR (200 MHz,CDCl₃) δ 7.40-7.30 (m, 5H), 5.20 (s, 2H), 3.90-3.80 (m, 4H), 2.60 (t, J7 Hz, 2H); ¹³C NMR (50 MHz, APT, CDCl₃) δ 136.0 (+), 128.5 (−), 128.0(−), 67.0 (+), 52.5 (+), 42.5 (+), 36.5 (+); IR (film) 1759, 1708 cm⁻¹.

7-Benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4.4]nonane (1d). A mixture of1c (52 g, no more than 225 mmol) and ethylene glycol (18.8 mL, 337.4mmol) in toluene (180 mL) with a catalytic amount of p-TsOH.H₂O (1.0 g,5.4 mmol) was refluxed in a Dean & Stark apparatus for 16 h. Thereaction mixture was then diluted with more toluene (250 mL) and washedwith saturated NaHCO₃ aq (150 mL) and brine (2×150 mL). The combinedaqueous layers were back-extracted with toluene (100 mL). The combinedorganic layers were dried and concentrated in vacuo to leave 79.6 g ofdark oil. The crude product was dissolved in EtOH (500 mL), and runningit through a bed of activated carbon (80 g), decolorized the resultantsolution. The charcoal was washed with more EtOH (1000 mL) and toluene(500 mL). The filtrate was concentrated in vacuo and further pumpedunder high vacuum for 1 h to yield 63.25 g (6.8% over theoretical yield)of 1d suitable for the next step without any further purification. R_(f)0.78 (EtOAc-iPrNH₂, 98:2, v/v); NMR (200 MHz, CDCl₃) δ 7.40-7.20 (m,5H), 5.20 (s, 2H), 4.00 (s, 4H), 3.60-3.50 (m, 2H), 3.50-3.40 (m, 2H),2.10-2.00 (m, 2H); ¹³C NMR (50 MHz, APT, CDCl₃) δ 137.0 (+), 128.5 (−),128 (−), 67.0 (+), 65.0 (+), 5.5 (+), 45.0 (+), 34.5 (+); IR (film) 1703cm⁻¹.

1,4-Dioxa-7-azaspiro[4.4]nonane (1e). A mixture of 1d (34.8 g, no morethan 124 mmol) and 10% Pd—C (14 g) in EtOH (90 mL) was hydrogenolyzed(60 psi) in a Parr shaker apparatus at room temperature for 1.5 h. Thecatalyst was filtered off, the solvent was evaporated in vacuo and theresidue was pumped under high vacuum for 20 min to yield 1e (15.9 g,quant. yield). R_(f) 0.14 (EtOAc-iPrNH₂, 95:5, v/v); ¹H NMR (200 MHz,CDCl₃) δ 4.00 (s, 4H), 3.10 (t, J 7 Hz, 2H), 2.90 (s, 2H), 2.00 (t, J 7Hz, 2H); ¹³C NMR (50 MHz, APT, CDCl₃) δ 64.5 (+), 55.0 (+), 45.5 (+),37.0 (+); IR (film) 3292 cm⁻¹.

(1R,2R)/(1S,2S)-1-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)cyclohexan-2-ol(2e). A mixture of 1e (23.5 g, no more than 182 mmol), cyclohexene oxide(23 mL, 220 mmol) and water (8 mL) was heated at 80° C. for 2 h. Thereaction mixture was then partitioned between 40% NaOH aq (60 mL) andEt₂O (120 mL). The basic aqueous layer was extracted twice more withEt₂O (2×120 mL). The combined organic extracts were dried andconcentrated in vacuo. The residue was then heated under high vacuum at50° C. for 1 h with stirring (to remove the excess of cyclohexene oxide)to yield 32.8 g of 2e (79% yield). R_(f) 0.33 (EtOAc-iPrNH₂, 98:2, v/v);¹³C NMR (50 MHz, APT, CDCl₃) δ 115.5 (+), 70.0 (−), 65.0 (−), 64.5 (+),57.0 (+), 46.5 (+), 36.0 (+), 33.5 (+), 25.0 (+), 24.0 (+), 21.5 (+); IR(film) 3457 cm⁻¹.

(1R,2R)/(1S,2S)-1-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-2-(3,4-dimethoxyphenoxy)cyclohexane in Et₂O (80 mL) was treated with ethereal HCl. Thesolvent was evaporated in vacuo and the residue was taken up with Et₂Oand triturated.(1R,2R)/(1S,2S)-1-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-2-(3,4-dimethoxyphenoxy)cyclohexanemonohydrochloride was precipitated from a mixture of CH₂Cl₂-Et₂O Asolution of(1R,2R)/(1S,2S)-1-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-2-(3,4-dimethoxyphenoxy)cyclohexane with 6 M HCl aq (50 mL) in 2-butanone (200 mL) wasrefluxed for 12 h. The butanone was evaporated in vacuo and the residualaqueous solution was diluted to 250 mL with water. The aqueous solutionwas extracted with Et₂O (2×200 mL) and then with CH₂Cl₂ (2×200 mL). Thepooled CH₂Cl₂ extracts were dried and the solvent was evaporated invacuo. The residual oil was azeotropically dried with toluene. Theresulting sticky product was triturated in Et₂O (500 mL), the resultantsolid was collected and solubilized in a small amount of CH₂Cl₂ (˜10mL), then addition of a large quantity of Et₂O (˜400 mL) triggeredrecrystallization. The solid was collected, dried under high vacuum for3 h to yield(1R,2R)/(1S,2S)-1-(3,4-Dimethoxyphenethoxy)-2-(3-ketopyrrolidinyl)cyclohexanemonohydrochloride (Compound 18)(1.9 g, 56% yield)

¹H NMR (400 MHz, free base, CDCl₃) δ 6.70 (m, 3H, Ar), 3.85 (2s, 6H,2×CH₃O), 3.80-1.10 (m, 20H, aliph); ¹³C NMR (75 MHz, APT, free base,CDCl₃) δ 215.21 (+), 148.57 (+), 147.27 (+), 131.64 (+), 120.61 (−),112.11 (−), 111.03 (−), 79.40 (−), 69.43 (+), 63.64 (−), 58.90 (+),55.76 (−), 55.70 (−), 48.00 (+), 37.63 (+), 36.31 (+), 29.00 (+), 27.07(+), 23.54 (+), 23.01 (+); HRMS (EI) mass calcd for C₂₀H₂₉O₄N:347.20966. found: 347.21046 (21.1%); Anal. (C₂₀H₃₀O₄NCl) H, N; C: calcd62.57. found, C, 60.32.

Preparation of(1R,2R)/(1S,2S)-1-(3,4-Dimethoxyphenethoxy)-2-(3-(R/S)-hydroxypyrrolidinyl)cyclohexane monohydrochloride (Compound 3)

To a chilled (0° C.) suspension of sodium borohydride (1.53 g, 40 mmol)in isopropanol (60 mL) was added slowly a solution of Compound 18 (6.14g, 16 mmol) in isopropanol (40 mL). The resultant mixture was stirred at0° C. for another 30 min and then was allowed to warm up to roomtemperature for 1 h. The reaction mixture was cooled to 0° C. again andslowly hydrolyzed with 1 M HCl aq (80 mL). The reaction mixture wasallowed to warm up to room temperature and was stirred overnight. Theorganic solvent was evaporated in vacuo, the residual aqueous layer wasdiluted with water to 150 mL and extracted with diethyl ether (1×150 mL)and dichloromethane (3×150 mL). The combined dichloromethane extractswere concentrated to 120 mL and treated with 0.25 M aq sodium hydroxide(100 mL). The aqueous layer was separated and extracted twice more withdichloromethane (2×150 mL). The combined dichloromethane extracts weredried over sodium sulfate and evaporated in vacuo. Purification bydry-column chromatography (ethyl acetate-hexanes, 2:1 to 4:1, +0.5% v/visopropylamine) provided 2.0 g (36% yield) of the title compound as afree base. 1.9 g of the free base was partitioned betweendichloromethane (24 mL) and 0.5 M HCl aq (24 mL). The aqueous layer wasseparated and extracted thrice more with dichloromethane (3×24 mL). Thecombined dichloromethane extracts were dried over sodium sulfate and thesolvent was evaporated in vacuo. Azeotropic distillation with benzene(2×25 mL) and drying under high vacuum provided the title compound as anoff-white hygroscopic solid (1.58 g). ¹H NMR (400 MHz, free base, CDCl₃)δ 6.80-6.70 (m, 3H, Ar), 4.20-1.10 (m, 22H, Aliph), 3.80 (2×s, 6H,2×CH₃O); ¹³C NMR (75 MHz, APT, free base, CDCl₃) δ 148.56 (+), 147.25(+), 131.83 (+), 120.66 (−), 112.25 (−), 111.00 (−), 79.30 (−), 79.11(−), 70.96 (−), 70.73 (−), 69.62 (+), 69.50 (+), 63.28 (−), 59.67 (+),59.35 (+), 55.80 (−), 55.71 (−), 48.70 (+), 48.44 (+), 36.35 (+), 34.33(+), 34.17 (+), 28.81 (+), 28.76 (+), 27.09 (+), 27.03 (+), 23.30 (+),23.22 (+), 22.92 (+), 22.86 (+); HRMS (EI) mass calcd for C₂₀H₃₁N₂O:349.22531. found: 349.22578 (100%); HPLC (Zorbax Extend C18, 150×4.6mmm, 5μ; 20-70% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 95.8%; CE99.8%.

EXAMPLE 4(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 4)

(1R,2R)/(1S,2S)-2-[(3R)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane was prepared according to Example 1. The titlecompound was formed by hydrogenolysis of(1R,2R)/(1S,2S)-2-[(3R)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexaneunder the conditions described in Example 1.

EXAMPLE 5(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexanemonohydrochloride (Compound 5)

(1R,2R)/(1S,2S)-2-[(3S)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane was prepared according to Example 1. The titlecompound was prepared by hydrogenolysis of(1R,2R)/(1S,2S)-2-[(3S)-benzyloxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexaneunder the conditions described in Example 1.

EXAMPLE 6(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride (Compound 6)

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride (compound 6) was prepared according to the method ofExample 1, but starting from 3-(S)-hydroxypyrrolidine.

EXAMPLE 7(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride (Compound 7)

(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemonohydrochloride (compound 7) was prepared according to the method ofExamples 1 and 2, but starting from 3-(S)-hydroxypyrrolidine.

COMPARATIVE EXAMPLE 8(1R,2R)/(1S,2S)-1-(3,4-Dimethoxyphenethoxy)-2-(1,4-dioxa-7-azaspiro[4,4]non-7-yl)cyclohexanemonohydrochloride (Compound 9)

To a chilled (0° C.) solution of 2e (4.62 g, 20 mmol) and triethylamine(2.64 g, 26 mmol) in dichloromethane (40 mL) was added dropwisemethanesulfonyl chloride (3.0 g, 26 mmol). The reaction mixture wasstirred at 0° C. for 45 min and then at room temperature for 2 h. Thereaction mixture was then washed with a mixture of water-saturatedsodium bicarbonate aq (1:1, v/v, 30 mL). The aqueous layer was collectedand back-extracted with dichloromethane (2×30 mL). The combined organicextracts were dried over sodium sulfate and the solvent was evaporatedin vacuo to yield the crude mesylate suitable for the next step withoutany further purification.

To sodium hydride (0.72 g, 80% dispersion in mineral oil, 24 mmol)suspended in DME (20 mL) was added a solution of 3,4-dimethoxyphenethylalcohol (4.46 g, 24 mmol) in DME (20 mL). The resulting mixture was thenstirred at room temperature for 2 h.

The mesylate in DME (40 mL) was added quickly to the alkoxide and theresultant mixture was refluxed under argon for 20 h. The cooled reactionmixture was quenched with water (60 mL) and the organic solvent wasevaporated in vacuo. The residual aqueous solution was acidified with10% HCl aq to pH 0.3 and extracted with diethyl ether (2×75 mL). Theaqueous layer was collected, basified to pH 7.0 with 5 M NaOH aq andextracted with diethyl ether (3×70 mL). The combined diethyl etherextracts were dried over sodium sulfate and the solvent was evaporatedin vacuo to yield 7.1 g (89% yield) of the title compound as a freebase.

The free amine (0.58 g, 1.48 mmol) was partitioned betweendichloromethane (8 mL) and 0.5 M HCl aq (8 mL). The aqueous layer wascollected and extracted twice more with dichloromethane (2×8 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to yield 0.62 g (98% yield) of the title compound. R_(f) 0.13(EtOAc-hexanes, 1:4, v/v, +0.5% v/v iPrNH₂); ¹H NMR (400 MHz, freeamine, CDCl₃) δ 6.75 (m, 3H, Ar), 3.86-1.16 (m, 24H, Aliph); ¹³C NMR (75MHz, APT, free amine, CDCl₃) δ 148.59 (+), 147.2 (+), 131.95 (+), 120.74(−), 115.24 (+), 112.26 (−), 111.04 (−), 79.10 (−), 69.78 (+), 64.22(+), 64.00 (−), 60.48 (+), 55.84 (−), 55.74 (−), 49.92 (+), 36.48 (+),35.84 (+), 28.60 (+), 26.92 (+), 23.01 (+), 22.74 (+); HRMS (EI) masscalcd for C₂₂H₃₃NO₅: 391.23587. found: 391.23546 (100%); HPLC (ZorbaxExtend C18, 150×4.6 mm, 5 μl; 20-7-% acetonitrile:10 mM phosphate buffer(pH 2.5)) 84.2%; CE 98.5%.

COMPARATIVE EXAMPLE 9(1R,2R)/(1S,2S)-1-(3,4-Dimethoxyphenethoxy)-2-(pyrrolidinyl)cyclohexanemonohydrochloride (Compound 10)

Pyrrolidine (10.5 g, 148 mmol), cyclohexene oxide (15 mL, 148 mmol) andwater (5 mL) were refluxed under nitrogen for 7 h. The cooled, orangemixture was partitioned between saturated sodium hydroxide aq (150 mL)and diethyl ether (150 mL). The aqueous layer was back-washed withdiethyl ether (75 mL) and the combined diethyl ether layers were driedover sodium sulfate. The diethyl ether was removed in vacuo the residualoil was vacuum distilled (bp 51° C. at full vacuum) to give(1R,2R)/(1S,2S)-2-(Pyrrolidinyl)cyclohexan-1-ol (21.9 g, 87%). ¹³C NMR(50 MHz, APT, CDCl₃) δ 70.47 (−), 64.82 (−), 47.44 (+), 33.15 (+), 25.11(+), 24.23 (+), 24.00 (+), 21.12 (+).

To a chilled (0° C.) solution of(1R,2R)/(1S,2S)-2-(Pyrrolidinyl)cyclohexan-1-ol (1.7 g, 10 mmol),triethylamine (1.8 mL, 13 mmol) in dichloromethane (50 mL) was addedneat methanesulfonyl chloride (1.0 mL, 13 mmol). The resultant mixturewas stirred at 0° C. for another 45 min and then was allowed to warm upto room temperature for 3 h. The reaction mixture was diluted withdichloromethane (50 mL) and washed with water (2×50 mL). The combinedwashings were back-extracted with dichloromethane (50 mL) and dried oversodium sulfate. Evaporation in vacuo of the solvent yielded the crudemesylate suitable for the next step without further purification.

To NaH (0.33 g, 11 mmol) in DME (15 mL) was added a solution of3,4-dimethoxyphenethyl alcohol (2.0 g, 11 mmol) in DME (15 mL). Theresultant mixture was stirred for 2 h at room temperature under argon.

The mesylate in DME (20 mL) was added to the alkoxide and the resultantreaction mixture was refluxed for 3 h. The solvent was evaporated invacuo, the residue was taken up with water (100 mL) and the pH wasadjusted to pH 1 with 1 M HCl aq. The acidic aqueous solution was thenextracted with diethyl ether (100 mL) and the pH was adjusted to pH 13.Extraction with diethyl ether (2×100 mL) provided the free base of thetitle compound. Treatment with ethereal hydrogen chloride followed bytrituration in diethyl ether yielded 1.0 g (27% yield) of the titlecompound as hydrochloride salt. ¹H NMR (400 MHz, CDCl₃) δ 11.60 (br s,1H, HN⁺), 6.70 (m, 3H, Ar), 3.80 (2×d, 2×6H, CH₃O), 3.70-1.05 (m, 22H,Aliph); ¹³C NMR (75 MHz, APT, CDCl₃) δ 148.72 (+), 147.41 (+), 131.32(+), 120.69 (−), 112.04 (−), 111.07 (−), 77.82 (−), 68.83 (+), 66.94(−), 55.87 (−), 53.12 (+), 51.76 (+), 35.92 (+), 30.25 (+), 28.30 (+),24.34 (+), 23.44 (+), 23.01 (+), 22.13 (+); MS (+LSIMS) M⁺+H 334 (100%);Anal. (C₂₀H₃₂O₃NCl) H, N; C: calcd, 64.94. found, 63.04.

COMPARATIVE EXAMPLE 10(1R,2R)-1-(3-(R)-Acetyloxypyrrolidinyl)-2-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride (Compound 17)

Acetyl chloride (5 mL; 70.31 mmol) was added dropwise into a solution of(3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl}pyrrolidin-3-olfree base (2.12 g; 5.49 mmol) in methylene chloride (50 mL) at 1° C. Thereaction was allowed to reach room temperature overnight. The reactionwas followed by TLC and visualized by iodine. The R_(f) of(1R,2R)-1-(3-(R)-acetyloxypyrrolidinyl)-2-(3,4-dimethoxyphenethoxy)cyclohexaneis 0.36 in methanol-methylene chloride (0.5:95, v/v). The excess ofacetyl chloride and the solvent were removed under reduced pressure andDCM (30 mL) was added to the remaining mixture. The organic layer waswashed with a saturated solution of sodium bicarbonate (30 mL), driedover magnesium sulfate and concentrated to yield the free base acetate(1.3 g, 4.35 mmol) in 61% yield.

COMPARATIVE EXAMPLE 11(1R,2S)/(1S,2R)-1-(3-(R/S)-Hydroxypyrrolidinyl)-2-(1-naphthalenethoxy)cyclohexanemonohydrochloride (Compound 25) Preparation of Intermediate Compound(1R,2S)/(1S,2R)-1-(3-Ketopyrrolidinyl)-2-(1-naphthalenethoxy)cyclohexanemonohydrochloride

To a flask containing Mg(ClO₄)₂ (2.14 g, 0.95 mmol) vacuum flame-dried,cooled and charged with argon, was added via cannula a solution of1-naphthaleneethanol (21.6 g, 125 mmol) in CH₃CN (15 mL). The resultantmixture was refluxed until all material had dissolved and thencyclohexene oxide (1.0 g, 10 mmol) was added over a period of 2.5 h. Thereaction mixture was then refluxed for 16 h, cooled to room temperatureand partitioned between water (150 mL), saturated NaHCO₃ aq (50 mL) andEt₂O (100 mL). The aqueous layer was collected and extracted twice withEt₂O (2×100 mL). The combined Et₂O extracts were back-washed with brine(50 ml), dried and concentrated in vacuo to yield 25.2 g of crudematerial, which solidified upon standing. The excess1-naphthaleneethanol was recovered by successive recrystallizations inEt₂O-hexanes (1:1, v/v). The resultant mother liquor (7.5 g) obtainedafter 3 recrystallizations was purified by chromatography using amixture of EtOAc-hexanes (1:5, v/v, +0.5% v/v iPrNH₂) to provide 1.5 g(55% yield) of crude(1R,2R)/(1S,2S)-2-(1-naphthalenethoxy)cyclohexan-1-ol, which was used inthe next step without further purification.

To a suspension of pyridinium chlorochromate (PCC) (4.78 g, 22.2 mmol)in CH₂Cl₂ (35 mL) was added at once a solution of(1R,2R)/(1S,2S)-2-(1-naphthalenethoxy)cyclohexan-1-ol (1.5 g, 5.5 mmol)in CH₂Cl₂ (5 mL). The resultant dark brown mixture was stirred at roomtemperature for 16 h, and then filtered through a plug of silica geltopped with Na₂SO₄. The plug was further rinsed with Et₂O (3×40 mL) andthe filtrate was concentrated in vacuo to yield 2.0 g of crude material.The crude material was applied to a dry column of silica gel and elutedwith a mixture of EtOAc-hexanes (1:6, v/v, +0.5% v/v iPrNH₂) to yield1.0 g of (2R/2S)-2-(1-Naphthalenethoxy)cyclohexan-1-one (68% yield). ¹³CNMR (50 MHz, APT, CDCl₃) δ 203.0 (+), 135.0 (+), 134.0 (+), 132 (+),129.0 (−), 127.0 (−), 125.5 (−), 125.0 (−), 123.5 (−), 113.0 (−), 83.0(−), 70.0 (+), 40.0 (+), 34.5 (+), 33.5 (+), 28.0 (+), 23.0 (+); IR(film) 1720 cm⁻¹.

(2R/2R)-2-(1-Naphthalenethoxy)cyclohexan-1-one (1.0 g, 3.7 mmol), 2e(1.2 g, 9.3 mmol) and poly(4-vinylpyridine) or PVP (0.4 g) in benzene(10 mL) were refluxed in a Dean-stark apparatus for 5 h. The cooledreaction mixture was then quickly transferred to a Parr shakerapparatus, Pd on activated carbon (0.2 g) was added and the mixture washydrogenated for 16 h. The catalyst was removed by filtration, thefiltrate was concentrated in vacuo and the resultant crude material(cis-trans, 87:13, area %/GC) was purified by dry-column chromatographywith a mixture of EtOAc-hexanes (1:2, v/v, +0.5% v/v iPrNH₂) to provide1.0 g (70% yield) of(1R,2S)/(1S,2R)-1-(1,4-dioxo-7-azaspiro[4.4]non-7-yl)-2-(1-naphthalenethoxy)cyclohexane,which was refluxed with 6 M HCl aq (20 mL) in 2-butanone (80 mL) for 16h. The cooled reaction mixture was concentrated in vacuo and the residuewas diluted with water (90 mL). The aqueous solution was then extractedwith Et₂O (2×50 mL) and CH₂Cl₂ (3×70 mL). The combined CH₂Cl₂ extractswere dried and the solvent was evaporated in vacuo. Trituration in Et₂Oprovided(1R,2S)/(1S,2R)-1-(3-Ketopyrrolidinyl)-2-(1-naphthalenethoxy)cyclohexanemonohydrochloride (0.82 g, 84% yield). mp 176-178° C.; ¹H NMR (400 MHz,CDCl₃) δ 12.53 (br s, 1H, HN⁺), 8.06-7.32 (m, 7H, Ar), 4.05-1.16 (m,20H, aliph); ¹³C NMR (75 MHz, APT, CDCl₃) δ 204.19 (+), 204.02 (+),134.99 (+), 134.90 (+), 133.65 (+), 131.94 (+), 131.85 (+), 128.71 (−),127.12 (−), 127.04 (−), 125.92 (−), 125.84 (−), 125.53 (−), 125.45 (−),123.75 (−), 123.68 (−), 72.49 (−), 71.79 (−), 68.39 (+), 68.24 (+),65.50 (−), 64.92 (−), 54.73 (+), 54.33 (+), 48.86 (+), 48.22 (+), 35.56(+), 35.12 (+), 32.91 (+), 26.81 (+), 26.77 (+), 24.00 (+), 22.53 (+),21.97 (+), 18.3 (+); HRMS (EI) mass Anal. (C₂₂H₂₈NO₂Cl) C, H, N.

Preparation of (Compound 25),(1R,2R)/(1S,2R)-1-(3-(R/S)-Hydroxypyrrolidinyl)-2-(1-naphthalenethoxy)cyclohexanemonohydrochloride

To a solution of(1R,2S)/(1S,2R)-1-(3-Ketopyrrolidinyl)-2-(1-naphthalenethoxy)cyclohexanemonohydrochloride (0.55 g, 1.5 mmol) in isopropanol (15 mL) was addedportion-wise sodium borohydride (0.3 g, 7.9 mmol). The resultantreaction mixture was stirred at room temperature for 16 h. The reactionmixture was quenched with 6 M HCl aq (4 mL) for 2 h and thenconcentrated in vacuo. The residual solid was taken up withdichloromethane (20 mL), the insoluble was filtered off and washed oncemore with dichloromethane (20 mL) and the combined filtrates weretreated with ethereal hydrogen chloride (20 mL). The solvents wereevaporated in vacuo and the residual oil was triturated in diethyl ether(80 mL) to yield 0.32 g (57% yield) of a hygrospcopic solid. ¹H NMR (400MHz, CDCl₃) δ 10.30 (br s, 1H, HN⁺), 8.10-7.30 (m, 7H, Ar), 5.40-1.00(m, 22H, Aliph); ¹³C NMR (75 MHz, APT, CDCl₃) δ 135.15 (+), 133.59 (+),131.92 (+), 128.53 (−), 127.05 (−), 126.85 (−), 125.80 (−), 125.40 (−),123.87 (−), 72.51 (−), 72.17 (−), 68.81 (−), 68.76 (−), 68.57 (+), 66.41(−), 66.25 (−), 65.19 (−), 59.75 (+), 59.08-58.68 (+), 50.43-49.82 (+),33.02 (+), 32.98 (+), 26.75 (+), 23.96 (+), 22.93-22.42 (+), 18.23 (+);MS (ES⁺) M⁺+H 340.1 (100%); HPLC (Zorbax Extend C18, 150×4.6 mm, 5μ;20-70% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 96.7%; CE 98.7%.

COMPARATIVE EXAMPLE 12(1R,2R)/(1S,2S)-[2-(4-Morpholinyl)-1-(2-Naphthenethoxy)]CyclohexaneMonohydrochloride (Compound 30)

(i) Morpholine (5 mL, 57 mmol), cyclohexene oxide (5.8 mL, 57 mmol) andwater (3 mL) were refluxed for 1.5 h. GC analysis showed the reaction tobe complete. The cooled mixture was partitioned between saturated NaOHsolution (50 mL) and ether (75 mL). The aqueous layer was backwashedwith ether (30 mL) and the combined ether layers were dried over sodiumsulfate. The ether was removed in vacuo to leave a yellow oil (9.83 g).The crude product, (1R,2R)/(1S,2S)-[2-(4-morpholinyl)]cyclohexanol, waspurified by vacuum distillation (b.p. 75-80° C. at full vacuum) to givea clear liquid (8.7 g). Yield 82.5%.

(ii) To a chilled (0° C.) solution of(1R,2R)/(1S,2S)-[2-(4-morpholinyl)]cyclohexanol (6.0 g, 32.4 mmol) andtriethylamine (6.8 mL, 48 mmol) in dichloromethane (100 mL) was addedvia cannula a solution of methanesulfonyl chloride (3.10 mL, 40 mmol) indichloromethane (50 mL). The addition was completed in 10 min., thereaction mixture was stirred for another hour at 0° C. and then at roomtemperature for 4 hours. The dichloromethane mixture was washed withwater (2×50 mL) and the combined aqueous washings back extracted withdichloromethane (50 mL). The combined organic layers were dried oversodium sulfate and concentrated in vacuo to provide 8.5 g (100% yield)of the crude mesylate.

(iii) To sodium hydride, 80% oil dispersion previously washed withhexanes (3×20 mL), (1.24 g, 51.6 mmol) in dry dimethylformamide (50 mL)was added via cannula a solution of 2-naphthenethanol (6.8 g, 40 mmol)in dry dimethylformamide (50 mL). Addition was followed by gas evolutionand, as the reaction mixture was stirred at room temperature, it beganto gel. The mesylate as prepared in (ii) above was dissolved indimethylformamide (50 mL) and the resulting solution was added quicklyvia cannula to the slurry of alcoholate. The reaction mixture was heatedto 80° C. and then the temperature reduced to 40° C. The resultingyellow solution was poured into ice-water (1500 mL) and extracted withethyl acetate (3×300 mL). The combined organic extracts were backwashedwith a saturated aqueous solution of sodium chloride (500 mL) and driedover sodium sulfate. Evaporation of the solvent in vacuo provided 13.4 gof an amber oil which was dissolved in water (150 mL) and the pH of thesolution was adjusted to pH 2 with aqueous 1M HCl. The acidic aqueoussolution was extracted with ethyl ether (2×100 mL) and then basified topH 10 with 50% sodium hydroxide aqueous solution. The basic aqueoussolution was extracted with ethyl ether (2×100 mL), the combined organiclayers were dried over sodium sulfate and concentrated in vacuo to leave7.16 g of the crude free aminoether. The crude product was purified bychromatography on silica gel 60 (70-230 mesh) with a mixture of ethylacetate-chloroform (1:1, v/v) as eluent to yield 4.37 g of the pure freebase. The product was dissolved in ethyl ether (80 mL) and converted tothe monohydrochloride salt by adding saturated solution of HCl in ethylether (80 mL). An oil came out of the solution, the solvent wasevaporated in vacuo and the residue dissolved in the minimum amount ofwarm ethyl alcohol, addition of a large volume of ethyl ether triggeredcrystallization. The crystals were collected to afford 3.83 g (31%yield) of the title compound, m.p. 158-160° C.

COMPARATIVE EXAMPLE 13(1R,2R)/(1S,2S)-[2-(4-Morpholinyl)-1-(4-Bromophenethoxy)]CyclohexaneMonohydrochloride (Compound 32)

(i) The starting trans-aminocyclohexanol is prepared according tocomparative example 12.

(ii) To a chilled (0° C.) solution of(±)-trans-[2-morpholinyl]cyclohexanol (3.0 g, 16.2 mmol) andtriethylamine (3.4 mL, 24 mmol) in dichloromethane (25 mL) was added viacannula a solution of methanesulfonyl chloride (1.55 mL, 20.0 mmol) indichloromethane (25 mL). The addition was completed in 5 min., thereaction mixture was stirred for another hour at 0° C. and then at roomtemperature for 2 hours. The reaction mixture was diluted withdichloromethane (50 mL) and washed with water (2×50 mL) and the combinedaqueous washings back extracted with dichloromethane (25 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to provide 4.7 g of the crude mesylate.

(iii) To sodium hydride, 80% oil dispersion, previously washed withhexanes (3×10 mL), (0.62 g, 25.8 mmol) in dry dimethylformamide (25 mL)was added via cannula a solution of 4-bromophenethylalcohol (4.0 g, 20mmol) in dimethylformamide (50 mL). Addition was followed by evolutionof gas and the reaction mixture was stirred at room temperature for 4hours. The mesylate as prepared in (ii) above was dissolved in drydimethylformamide (50 mL) and the resulting solution was added quickly(3 min.) via cannula to the slurry of alcoholate. The reaction mixturewas heated to 80° C. for 2 hours, then the temperature was reduced to35° C. and the reaction stirred overnight. The reaction mixture waspoured into ice-water (800 mL) and extracted with ethyl acetate (3×200mL). The combined organic extracts were backwashed with a saturatedaqueous solution of sodium chloride (150 mL) and dried over sodiumsulfate. Evaporation of the solvent in vacuo provided 7.4 g of an oilwhich was dissolved in ether (80 mL) was treated with a saturatedsolution of HCl in ether. An oil came out of solution, the solvent wasevaporated in vacuo and the residue was dissolved in water (100 mL). Theacidic aqueous solution was extracted with ethyl ether (2×50 mL) andthen basified to pH 10 with 50% sodium hydroxide aqueous solution. Thebasic aqueous solution was extracted with ethyl ether (2×50 mL), thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to leave 3.67 g of the crude free amino ether. The crudeproduct was purified by chromatography on silica gel 60 (70-230 mesh)with a mixture of ethyl acetate-dichloromethane (1:1, v/v) as eluent toprovide the pure free base. The product was dissolved in ethyl ether (30mL) and converted to the monohydrochloride salt by adding a saturatedsolution of HCl in ethyl ether (30 mL). The solvent was evaporated andthe residue dissolved in the minimum amount of ethyl alcohol, additionof a large volume of ethyl ether triggered crystallization. The crystalswere collected to afford 1.31 g of the title compound, m.p. 148-151° C.

COMPARATIVE EXAMPLE 14(1R,2R)/(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexanemonohydrochloride (Compound 41)

(vi) To a chilled (0° C.) solution of(1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (2e)(27.77 g, 120 mmol) and triethylamine (22 mL, 156 mmol) indichloromethane (240 mL) was added methanesulfonyl chloride (12.32 mL,156 mmol). The reaction mixture was stirred at 0° C. for 45 min. andthen at room temperature for 3 hours. The reaction mixture was washedwith water (2×100 mL) and the combined washings were back-extracted withdichloromethane (120 mL). The combined organic extracts were dried oversodium sulfate and the solvent was evaporated in vacuo to yield thecrude mesylate which was further pumped under high vacuum for 4 hoursprior to use in step (ix) below.

(vii) 2,6-Dichlorophenethyl alcohol: a suspension of lithium aluminumhydride (13.75 g, 365.75 mmol) in anhydrous diethyl ether (500 mL) wasadded via a powder addition funnel 2,6-dichlorophenylacetic acid (50 g,243.75 mmol). The resulting reaction mixture was refluxed for 16 hoursand then quenched by slow addition of a sodium sulfate saturated aqueoussolution (25 mL). The resulting slurry was stirred for 3 hours and thenfiltered, the insoluble was carefully washed with diethyl ether (2×100mL). The combined ether filtrates were dried over sodium sulfate and thesolvent was evaporated in vacuo to yield 38.6 g (85% yield) of the titlecompound.

(viii) To sodium hydride (144 mmol, 4.32 g, 80% oil dispersion) inanhydrous ethylene glycol dimethyl ether (80 mL) was added a solution of2,6-dichlorophenethyl alcohol (27.65 g, 144 mmol) in anhydrous ethyleneglycol dimethyl ether (80 mL). The resulting mixture was stirred at roomtemperature under argon atmosphere for 4 hours.

(ix)(1R,2R)/(1S,2S)-2-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclohexane:The mesylate from (vi) in anhydrous ethylene glycol dimethyl ether (80mL) was added quickly to the alkoxide mixture (viii) and the resultingmixture was readily refluxed for 66 hours. The cooled reaction mixturewas poured into water (200 mL) and the organic solvent was evaporated invacuo. The residual aqueous solution was diluted with more water to avolume of 700 mL, acidified to pH 0.5 with 6M HCl aqueous solution andextracted with diethyl ether (2×600 mL). The pH of the aqueous layer wasadjusted to pH 5.9 and then the aqueous solution was extracted withdiethyl ether (700 mL). The organic extract was dried over sodiumsulfate and the solvent was evaporated in vacuo to yield 34.0 g of thetitle compound (70% yield).

(x)(1R,2R)/(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexanemonohydrochloride: A mixture of(1R,2R)/(1S,2S)-2-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclohexane(15.85 g, 38.9 mmol, step ix) and 6M HCl aqueous solution (100 mL) in2-butanone (400 mL) was refluxed for 16 hours. The cooled reactionmixture was diluted with water (100 mL) and the organic solvent wasevaporated in vacuo. The organic layer was further diluted with water(400 mL), extracted with diethyl ether (500 mL) and with dichloromethane(2×600 mL). The combined dichloromethane extracts were dried over sodiumsulfate and the solvent was evaporated in vacuo. Azeotropic distillationwith toluene provided the title compound which was further dried underhigh vacuum for 15 min. The hydrochloride salt was crystallized bytriturating in diethyl ether, the crystals were collected andrecrystallized from a mixture of ethanol-diethyl ether to yield 11.85 gof pure product (77% yield), having the correct elemental analysis.

COMPARATIVE EXAMPLE 15

(1R,2R)/(1S,2S)-2-(3-Acetoxypyrrolidinyl)-1-(1-naphthenethoxy)cyclohexanemonohydrochloride (Compound 43)

(i)(1R,2R)/(1S,2S)-2-(3-Hydroxypyrrolidinyl)-1-(1-naphthenethoxy)cyclohexanemonohydrochloride: To a chilled (0° C.) solution of sodium borohydridein isopropanol (20 mL) was added a solution of(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)cyclohexanemonohydrochloride (1.4 g, 3.75 mmol) in isopropanol (30 mL). Theresulting mixture was stirred at 0° C. for 15 min. and then 30 min. atroom temperature. The reaction was quenched by addition of water, thereaction mixture was evaporated to dryness and the residue was washedwith dichloromethane (2×20 mL). The dichloromethane washings were driedover sodium sulfate and the solvent was evaporated in vacuo to yield thetitle compound.

(ii)(1R,2R)/(1S,2S)-2-(3-Acetoxypyrrolidinyl)-1-(1-naphthenethoxy)cyclohexanemonohydrochloride: The intermediate alcohol (i) was then refluxed inacetic anhydride (15 mL) for 2 hours. The excess acetic anhydride wasremoved in vacuo; the residue was taken up with water (100 mL) andextracted with diethyl ether (2×30 mL). The aqueous solution wasbasified to pH 8.0 and extracted with diethyl ether (3×50 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo. The residual oil was dissolved in a small amountof dichloromethane and a large volume of diethyl ether was added inorder to trigger crystallization of 1.0 g (65% yield) of the titlecompound

COMPARATIVE EXAMPLE 16(1R,2R)/(1S,2S)-2-(3-Thiazolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexanemonohydrochloride (Compound 48)

(i) (1R,2R)/(1S,2S)-2-(3-Thiazolidinyl)cyclohexanol: To anhydrousmagnesium perchlorate (12.93 g, 53.3 mmol) was added a solution ofcyclohexene oxide (6.1 mL, 58.6 mmol) in anhydrous acetonitrile (25 mL)and the resulting mixture was stirred at room temperature for 20 min.Then a solution of thiazolidine (5.16 g, 55.0 mmol) in anhydrousacetonitrile was added and the reaction mixture was heated at 35° C. for16 hours. The reaction mixture was concentrated in vacuo and the residuewas partitioned between water (350 mL) and diethyl ether (350 mL). Theaqueous layer was separated and extracted once more with diethyl ether(350 mL). The combined organic extracts were dried over sodium sulfateand concentrated in vacuo to provide the crude product. The crudeaminoalcohol was purified by dry-column chromatography with a mixture ofethyl acetate-hexanes (1:1, v/v) as eluent to yield 4.83 g (47% yield)of the title compound.

(ii) To a chilled (0° C.) solution of(1R,2R)/(1S,2S)-2-(3-thiazolidinyl)cyclohexanol (3.17 g, 16.9 mmol) andtriethylamine (3.08 mL, 22.0 mmol) in dichloromethane (30 mL) was addeddropwise methanesulfonyl chloride (1.74 mL, 22.0 mmol). The reactionmixture was stirred at 0° C. for one hour and then at ambienttemperature for 3 hours. The reaction mixture was diluted withdichloromethane (20 mL) and washed with water (2×30 mL). The combinedwashings were back-extracted with dichloromethane (25 mL) and thecombined organic extracts were dried over sodium sulfate. Evaporation ofthe solvent in vacuo yielded the mesylate suitable for the next stepwithout any further purification.

(iii) To sodium hydride, 80% oil dispersion (608 mg, 20.28 mmol) inethylene glycol dimethyl ether (30 mL) was added a solution of2,6-dichlorophenethyl alcohol (3.87 g, 20.28 mmol, example 4, step vii)in ethyleneglycol dimethyl ether (15 mL). The resulting mixture wasstirred at room temperature under argon atmosphere for 2 hours.

(iv)(1R,2R)/(1S,2S)-2-(3-Thiazolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexanemonohydrochloride: The mesylate (ii) in ethylene glycol dimethyl ether(15 mL) was added quickly to the alkoxide (iii) and the reaction mixturewas refluxed for 40 hours. The cooled reaction mixture was poured intowater (100 mL) and the organic solvent was evaporated in vacuo. Theresidual aqueous solution was diluted with more water (100 mL) and thepH was adjusted to pH 1.5. The acidic aqueous solution was extractedwith diethyl ether (3×100 mL), the combined organic extracts were driedover sodium sulfate and the solvent was removed in vacuo to provide thecrude free base. The product was purified by dry-column chromatographywith a mixture of ethyl acetate-hexanes (1:10, v/v) as eluent to yield2.4 g of the crude free aminoether. The pure product (1.0 g) wasconverted to the hydrochloride salt by treatment with ethereal HCl andthe resulting salt was recrystallized from a mixture of acetone-diethylether to yield 0.69 g of the title compound.

COMPARATIVE EXAMPLE 17(1R,2R)/(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,2-diphenylethoxy)cyclohexanemonohydrochloride (Compound 47)

(vi) To a chilled (0° C.) solution of(1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (2e)(2.0 g, 8.8 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane(30 mL) was added methanesulfonyl chloride (0.9 mL, 11.44 mmol). Thereaction mixture was stirred at 0° C. for 45 min. and then at roomtemperature for 3 hours. The reaction mixture was diluted withdichloromethane (25 mL), washed with water (2×25 mL) and the combinedwashings were back-extracted with dichloromethane (25 mL). The combinedorganic extracts were dried over sodium sulfate and the solvent wasevaporated in vacuo to yield the crude mesylate which was further pumpedunder high vacuum for 30 min. prior to use in step (ix) below.

(vii) (2,2-Diphenyl)ethyl alcohol: To lithium aluminum hydride (2.85 g,23.56 mmol) in anhydrous diethyl ether (150 mL) was added, as a powder,diphenylacetic acid (5.0 g, 56 mmol). The resulting reaction mixture wasgently refluxed for one hour. The reaction was quenched with sodiumsulfate saturated aqueous solution and the resulting precipitate wasfiltered off. The filtrate was concentrated in vacuo to yield 4.0 g (86%yield) of the title compound.

(viii) To sodium hydride, previously washed with hexanes, (253 mg, 10.56mmol) in suspension in ethylene glycol dimethyl ether (15 mL) was addeda solution of 2,2-diphenylethyl alcohol (2.09 g, 10.56 mmol, step vii)in ethylene glycol dimethyl ether (15 mL). The resulting mixture wasstirred at room temperature under argon atmosphere for 30 min.

(ix)(1R,2R)/(1S,2S)-2-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)-1-(2,2-diphenylethoxy)cyclohexane:The mesylate from (vi) in ethylene glycol dimethyl ether (20 mL) wasadded quickly to the alkoxide (viii) and the reaction mixture wasrefluxed for 5 days. The cooled reaction mixture was concentrated invacuo, the residue was taken up with water (50 mL) and the pH wasadjusted to pH 1.0 with 6M HCl aqueous solution. The acidic aqueoussolution was extracted with diethyl ether (2×50 mL), the aqueous layerwas collected and basified to pH 6.0. Extraction with diethyl ether(2×50 mL) followed by drying over sodium sulfate and evaporation of thesolvent in vacuo yielded 1.55 g (43% yield) of the title compound.

(x)(1R,2R)/(1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,2-diphenylethoxy)cyclohexanemonohydrochloride: A mixture of(1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(2,2-diphenylethoxy)cyclohexane(1.55 g, 3.8 mmol) in 6M HCl-butanone(1:4, v/v, 50 mL) was refluxed for2 hours. The butanone was evaporated in vacuo and the residue was takenup with water (50 mL). The aqueous solution was extracted with diethylether (2×50 mL); the aqueous layer was collected and extracted withdichloromethane (2×50 mL). The combined dichloromethane extracts weredried over sodium sulfate and concentrated in vacuo to yield the crudetitle compound. The product was crystallized by triturating in diethylether and reprecipitated from a mixture of dichloromethane-diethyl etherto yield 1.21 g (80% yield) of the title compound, having the correctelemental analysis.

General Experimental Procedures

Melting points were determined on a Fisher-Johns apparatus and areuncorrected. NMR spectra were acquired in the indicated solvent on aBrucker AC-200, Varian XL-300, Brucker AV-300 or AV-400. Mass spectrawere recorded for EI on a Kratos MS50, for FAB/LSIMS on a Kratos ConceptIIHQ and for ES on a Micromass (Waters) Quattro (I) MSMS, connected to aHP1090 Series 2 LC (Agilent), controlled by Masslynx version 3.3software. Elemental analyses were performed on an Element Analyzer 1108by D. & H. Malhow, University of Alberta, Edmonton, AB. Where analysesare indicated only by symbols of the elements, analytical results werewithin ±0.4% of the theoretical values. Whenever elemental analyses werenot available, purity was determined by HPLC and capillaryelectrophoresis (CE). HPLC analyses were performed using a Gilson HPLCsystem (Gilson, Middleton, Wis.) with UV detection at 200 nm. A C₁₈column with 150×4.6 mm, 5μ particle size was used. The mobile phase wasdelivered isocratically or as a gradient at a flow rate of 1 mL/min andconsisted of a combination of phosphate buffer (low or high pH) andacetonitrile. Samples were prepared at ˜100 μg/mL in mobile phase and 20μL were injected into the HPLC. Purity was expressed in area %. CEanalyses were performed using a P/ACE System MDQ (Beckman Coulter,Fullerton, Calif.). Uncoated silica capillaries with 60 (50 to detector)cm length and 75 μm internal diameter were used. The run buffer used was100 mM sodium phosphate (pH 2.5). The separation voltage was either 23or 25 kV (normal polarity) and the capillary cartridge temperature wasmaintained at 20° C. Samples (˜0.5 mg/mL in water) were injected bypressure at 0.5 psi for 6 seconds. Detection was by UV at 200 or 213 nm.Purity was expressed in area %. IR were recorded on a Perkin-Elmer 983Gspectrophotometer. Optical rotations were performed by F. Hoffman-LaRoche Ltd (CH, Basel). Thin layer chromatography (TLC) was performed onE. Merck, TLC aluminum sheets 20×20 cm, Silica gel 60 F₂₅₄ plates. Flashchromatography⁴¹ was performed on E.M. Science silica gel 60 (70-230mesh). Dry flash chromatography⁴² was performed with Sigma silica geltype H. Chromatotron chromatography (Harisson Research, USA) wasperformed on 4 mm plate with EM Science silica gel 60P F₂₅₄ with Gypsumor aluminum oxide 60P F₂₅₄ with Gypsum (type E). Preparative HPLC wereperformed on a Waters Delta Prep 4000 with a cartridge column (porasil,10 μm, 125 Å, 40 mm×100 mm). GC analyses were performed on a HewlettPackard HP 6890 equipped with 30 m×0.25 mm×0.25 μm capillary columnHP-35 (crosslinked 35% PH ME siloxane) and a flame-ionization detector.High-boiling solvents (DMF, DMSO) were Sure/Seal™ from Aldrich, andtetrahydrofuran (THF) and ethylene glycol dimethyl ether (DME) weredistilled from sodium-benzophenone ketyl. Organic extracts were driedwith Na₂SO₄ unless otherwise noted. All moisture sensitive reactionswere performed in dried glassware under a nitrogen or argon atmosphere.

Biological Activity Data

Assessment of Antiarrhythmic Efficacy

Antiarrhythmic efficacy may be assessed by investigating the effect of acompound on the incidence of cardiac arrhythmias in anesthetized ratssubjected to coronary artery occlusion. Rats weighing 200-300 gms aresubjected to preparative surgery and assigned to groups in a randomblock design. In each case, the animal is anesthetized withpentobarbital during surgical preparation. The left carotid artery iscannulated for measurement of mean arterial blood pressure andwithdrawal of blood samples. The left jugular vein is also cannulatedfor injection of drugs. The thoracic cavity is opened and a polyethyleneoccluder loosely placed around the left anterior descending coronaryartery. The thoracic cavity is then closed. An ECG is recorded byinsertion of electrodes placed along the anatomical axis of the heart.In a random and double-blind manner, an infusion of vehicle or thecompound to be tested is given about 15 min post-surgery. After 5minutes infusion, the occluder is pulled so as to produce a coronaryartery occlusion. ECG, arrhythmias, blood pressure, heart rate andmortality are monitored for 15 minutes after occlusion. Arrhythmias arerecorded as ventricular tachycardia (VT) and ventricular fibrillation(VF) and scored according to Curtis, M. J. and Walker, M. J. A.,Cardiovasc. Res. 22:656 (1988) (see Table 1).

TABLE 1 Score Description 0 0-49 VPBs 1 50-499 VPBs 2 >499 VPBs and/or 1episode of spontaneously reverting VT or VF 3 >1 episode of VT or VF orboth (>60 s total combined duration) 4 VT or VF or both (60-119 s totalcombined duration) 5 VT or VF or both (>119 s total combined duration) 6fatal VF starting at >15 min after occlusion 7 fatal VF starting atbetween 4 min and 14 min 59 s after occlusion 8 fatal VF starting atbetween 1 min and 3 min 59 s after occlusion 9 fatal VF starting <1 minafter occlusion Where: VPB = ventricular premature beats VT =ventricular tachycardia VF = ventricular fibrillation

Rats are excluded from the study if they did not exhibit pre-occlusionserum potassium concentrations within the range of 2.9-3.9 mM. Occlusionis associated with increases in R-wave height and “S-T” segmentelevation; and an occluded zone (measured after death by cardiogreen dyeperfusion) in the range of 25%-50% of total left-ventricular weight.

Results of the test compounds may be expressed as values of a giveninfusion rate in micromol/kg/min. (ED₅₀AA) which will reduce thearrhythmia score in treated animals to 50% of that shown by animalstreated only with the vehicle in which the test compound(s) isdissolved.

Table 4, column 6 shows the ED₅₀AA result of tests of the compounds 1 to7 according to the invention in micromol/kg/min. Table 5, column 6 showsthe ED₅₀AA result of tests of the comparative examples compounds 8 to 48in micromol/kg/min.

Measurement of Cardiovascular and Behavioral Effects

Preparative surgery is performed in Sprague Dawley rats weighing 200-300gm and anaesthetized with 65 mg/kg (i.p.) pentobarbital. The femoralartery and vein are cannulated using polyethylene (PE)-10 tubing. Priorto surgery, this PE-10 tubing had been annealed to a wider gauge (PE-50)tubing for externalization. The cannulated PE-10/PE-50 tubing is passedthrough a trocar and exteriorised together with three (lead II) limb ECGleads (see below). The trocar is threaded under the skin of the back andout through a small incision at the mid-scapular region. A ground ECGelectrode is inserted subcutaneously using a 20 gauge needle with thelead wire threaded through it. To place the other ECG electrodes, asmall incision is made in the anterior chest region over the heart andECG leads are inserted into the subcutaneous muscle layer in the regionof the heart using a 20 guage needle. Other ECG leads are inserted intothe subcutaneous muscle layer in the region near the base of the neckand shoulder (right side). The animal is returned to a cleanrecovery-cage with free access to food and water. The treatment andobservational period for each animal commenced after a 24-hour recoveryperiod.

A 15 min observational period is recorded followed by the intravenousinfusion regime of the test compound at an initial dose of 2.0μmol/kg/min (at 1 ml/hr). This rate is doubled every 5 minutes until oneof the following effects is observed:

a) partial or complete convulsions

b) severe arrhythmias

c) bradycardia below 120 beats/min

d) hypotension below 50 mmHg

e) the dose exceeds 32 times the initial starting dose (i.e., 64μmol/kg/min).

Blood pressure (BP), heart rate (HR) and ECG variables are continuouslyrecorded while behavioral responses are also monitored and the totalaccumulative drug dose and drug infusion rate at which the response(such as convulsion, piloerection, ataxia, restlessness, compulsivechewing, lip-smacking, wet dog shake etc.) occurred are recorded.

Blood Samples

Estimates of plasma concentrations of the test compound are determinedby removing a 0.5 ml blood sample at the end of the experiment. Bloodsamples are centrifuged for 5 min at 4600×g and the plasma decanted.Brain tissue samples are also extracted and kept frozen (−20° C.) alongwith the plasma samples for chemical analysis.

Data Analysis

Electrocardiograph (ECG) parameters: PR, QRS, QT₁ (peak of T-wave), QT₂(midpoint of T-wave deflection) and hemodynamic parameters: BP and HRare analyzed using the automated analysis function in LabView (NationalInstruments) with a customized autoanalysis software (NortranPharmaceuticals). The infused dose producing 25% from control (D₂₅) forall recorded ECG variables is determined.

Results of the tests can be expressed as D₂₅ (micromol/kg) which are thedoses required to produce a 25% increase in the ECG parameter measured.The increases in P-R interval and QRS interval indicate cardiac sodiumchannel blockade while the increase in Q-T interval indicates cardiacpotassium channel blockade.

Electrophysiological Test (In Vivo)

This experiment determines the potency of the test compound for itseffects on haemodynamic and electrophysiological parameters undernon-ischemic conditions.

Methods

Surgical Preparation

Male Sprague-Dawley rats weighing between 250-350 g are used. They arerandomly selected from a single group and anesthetized withpentobarbital (65 mg/kg, ip.) with additional anesthetic given ifnecessary.

The trachea is cannulated and the rat is artificially ventilated at astroke volume of 10 ml/kg, 60 strokes/minute. The right external jugularvein and the left carotid artery are cannulated for intravenousinjections of compounds and blood pressure (BP) recording, respectively.

Needle electrodes are subcutaneously inserted along the suspectedanatomical axis (right atrium to apex) of the heart for ECG measurement.The superior electrode is placed at the level of the right clavicleabout 0.5 cm from the midline, while the inferior electrode is placed onthe left side of the thorax, 0.5 cm from the midline and at the level ofthe ninth rib.

Two Teflon-coated silver electrodes are inserted through the chest wallusing 27G needles as guides and implanted in the epicardium of leftventricle (4-5 mm apart). Square pulse stimulation is provided by astimulator controlled by a computer. In-house programmed software isused to determine the following: threshold current (iT) for induction ofextra systoles, maximum following frequency (MFF), effective refractoryperiod (ERP) and ventricular flutter threshold (VTt). Briefly, iT ismeasured as the minimal current (in μA) of a square wave stimulusrequired to capture and pace the heart at a frequency of 7.5 Hz and apulse width of 0.5 msec; ERP is the minimum delay (in msec) for a secondstimulus required to cause an extra systole with the heart entrained ata frequency of 7.5 Hz (1.5×iT and 0.2 msec pulse width), MFF is themaximum stimulation frequency (in Hz) at which the heart is unable tofollow stimulation (1.5×1T and 0.2 msec pulse width); VTt is the minimumpulse current (in μA) to evoke a sustained episode of VT (0.2 msec pulsewidth and 50 Hz) (Howard, P. G. and Walker, M. J. A., Proc. West.Pharmacol. Soc. 33:123-127 (1990)).

Blood pressure (BP) and electrocardiographic (ECG) parameters arerecorded and analyzed using LabView (National Instruments) with acustomized autoanalysis software (Nortran Pharmaceuticals Inc.) tocalculate mean BP (mmHg, ⅔ diastolic+⅓ systolic blood pressure), HR(bpm, 60/R-R interval); PR (msec, the interval from the beginning of theP-wave to the peak of the R-wave), QRS (msec, the interval from thebeginning of the R-wave due to lack of Q wave in rat ECG, to the peak ofthe S-wave), QT (msec, the interval from the beginning of the R-wave tothe peak of the T-wave).

Experimental Protocol

The initial infusion dose is chosen based on a previous toxicology studyof the test compound in conscious rats. This is an infusion dose thatdid not produce a 10% change from pre-drug levels in haemodynamic or ECGparameters.

The animal is left to stabilize prior to the infusion treatmentaccording to a predetermined random and blind table. The initialinfusion treatment is started at a rate of 0.5 ml/hr/300 g (i.e., 0.5μmol/kg/min). Each infusion dose is doubled (in rate) every 5 minutes.All experiments are terminated at 32 ml/hr/300 g (i.e., 32 μmol/kg/min).Electrical stimulation protocols are initiated during the last twominutes of each infusion level.

Data Analyses

Responses to test compounds are calculated as percent changes frompre-infusion values; this normalization is used to reduce individualvariation. The mean values of BP and ECG parameters at immediatelybefore the electrical stimulation period (i.e., 3 min post-infusion) areused to construct cumulative dose-response curves. Data points are fitusing lines of best fit with minimum residual sum of squares (leastsquares; SlideWrite program; Advanced Graphics Software, Inc.). D₂₅'s(infused dose that produced 25% change from pre-infusion value) areinterpolated from individual cumulative dose-response curves and used asindicators for determining the potency of compounds of the presentinvention.

Canine Vagal-AF Model General Methods

Mongrel dogs of either sex weighing 15-49 kg are anesthetized withmorphine (2 mg/kg im initially, followed by 0.5 mg/kg IV every 2 h) andα-chloralose (120 mg/kg IV followed by an infusion of 29.25 mg/kg/h;St.-Georges et al., 1997). Dogs are ventilated mechanically with roomair supplemented with oxygen via an endotracheal tube at 20 to 25breaths/minute with a tidal volume obtained from a nomogram. Arterialblood gases are measured and kept in the physiological range (SAO₂>90%,pH 7.30-7.45). Catheters are inserted into the femoral artery for bloodpressure recording and blood gas measurement, and into both femoralveins for drug administration and venous sampling. Catheters are keptpatent with heparinized 0.9% saline solution. Body temperature ismaintained at 37-40° C. with a heating blanket.

The heart is exposed via a medial thoracotomy and a pericardial cradleis created. Three bipolar stainless steel, Teflon™-coated electrodes areinserted into the right atria for recording and stimulation, and one isinserted into the left atrial appendage for recording. A programmablestimulator (Digital Cardiovascular Instruments, Berkeley, Calif.) isused to stimulate the right atrium with 2 ms, twice diastolic thresholdpulses. Two stainless steel, Teflon™-coated electrodes are inserted intothe left ventricle, one for recording and the other for stimulation. Aventricular demand pacemaker (GBM 5880, Medtronics, Minneapolis, Minn.)is used to stimulate the ventricles at 90 beats/minute when (particularduring vagal-AF) the ventricular rate became excessively slow. A P23 IDtransducer, electrophysiological amplifier (Bloom Associates, FlyingHills, Pa.) and paper recorder (Astromed MT-95000, Toronto, ON, Canada)are used to record ECG leads II and III, atrial and ventricularelectrograms, blood pressure and stimulation artefacts. The vagi areisolated in the neck, doubly-ligated and divided, and electrodesinserted in each nerve (see below). To block changes in β-adrenergiceffects on the heart, nadolol is administered as an initial dose of 0.5mg/kg iv, followed by 0.25 mg/kg IV every two hours.

Atrial Fibrillation Model

Drug effects to terminate sustained AF maintained during continuousvagal nerve stimulation are assessed. Unipolar hook electrodes(stainless steel insulated with Teflon™, coated except for the distal1-2 cm) are inserted via a 21 gauge needle within and parallel to theshaft of each nerve. In most experiments, unipolar stimuli are appliedwith a stimulator (model DS-9F, Grass Instruments, Quincy, Mass.) set todeliver 0.1 ms square-wave pulses at 10 Hz and a voltage 60% of thatrequired to produce asystole. In some experiments, bipolar stimulationis used. The voltage required to produce asystole ranged between 3-20volts. Under control conditions, a short burst of rapid atrial pacing(10 Hz, four times diastolic threshold) is delivered to induce AF whichis ordinarily sustained for more than 20 minutes. The vagal stimulationvoltage is adjusted under control conditions, and then readjusted aftereach treatment to maintain the same bradycardic effect. AF is defined asrapid (>500 minute under control conditions), irregular atrial rhythmwith varying electrogram morphology.

Measurement of Electrophysiological Variables and Vagal Response

Diastolic threshold current is determined at a basic cycle length of 300ms by increasing the current 0.1 mA incrementally until stable captureis obtained. For subsequent protocols current is set to twice diastolicthreshold. Atrial and ventricular ERP is measured with the extrastimulusmethod, over a range of S1S2 intervals at a basic cycle length of 300ms. A premature extrastimulus S2 is introduced every 15 basic stimuli.The S1S2 interval is increased in 5 ms increments until captureoccurred, with the longest S1S2 interval consistently failing to producea propagated response defining ERP. Diastolic threshold and ERP aredetermined in duplicate and averaged to give a single value. Thesevalues are generally within 5 ms. The interval between the stimulusartefact and the peak of the local electrogram is measured as an indexof conduction velocity. AF cycle length (AFCL) is measured duringvagal-AF by counting the number of cycles (number of beats—1) over a2-second interval at each of the atrial recording sites. The three AFCLsmeasurements are averaged to obtain an overall mean AFCL for eachexperimental condition.

The stimulus voltage-heart rate relationship for vagal nerve stimulationis determined under control conditions in most experiments. The vagalnerves are stimulated as described above with various voltages todetermine the voltage which caused asystole (defined as a sinus pausegreater than 3 seconds). The response to vagal nerve stimulation isconfirmed under each experimental condition and the voltage adjusted tomaintain the heart rate response to vagal nerve stimulation constant. Incases in which is not possible to produce asystole, vagal nervestimulation is adjusted to a voltage which allowed two 20-minuteepisodes of vagal-AF to be maintained under control conditions (seebelow).

Experimental Protocols

One of the experimental groups studied is summarized in Table 3. Eachdog received only one drug at doses indicated in Table 3. The firstseries of experiments are dose ranging studies, followed by blindedstudy in which 1-3 doses are given. All drugs are administered IV via aninfusion pump, with drug solutions prepared freshly in plasticcontainers on the day of the experiment. Vagal stimulation parametersare defined under control conditions as described above, and maintenanceof AF during 20 minutes of vagal nerve stimulation under controlconditions is verified. After the termination of AF, the diastolicthreshold and ERP of the atrium and ventricle are determined.Subsequently, these variables are reassessed in the atrium under vagalnerve stimulation. Electrophysiological testing usually took 15-20minutes. The heart rate response to vagal nerve stimulation is confirmedand the vagal-AF/electrophysiological testing protocol is repeated. Apre-drug blood sample is obtained and vagal-AF reinstituted. Fiveminutes later, one of the treatments is administered at doses shown inTable 2. The total dose is infused over 5 minutes and a blood sampleobtained immediately thereafter. No maintenance infusion is given. If AFterminated within 15 minutes, the electrophysiological measurementsobtained under control conditions are repeated and a blood sample isobtained. If AF is not terminated by the first dose (within 15 minutes),a blood sample is obtained and vagal stimulation is discontinued toallow a return to sinus rhythm. The electrophysiological measurementsare repeated and a third and final blood sample for this dose isobtained. AF is reinitiated and the vagal-AF/druginfusion/electrophysiological testing protocol is repeated until AF isterminated by the drug.

Statistical Analysis

Group data are expressed as the mean±SEM. Statistical analysis iscarried out for effective doses for AFCL, and ERP using a t-test with aBonferroini correction for multiple comparisons. Drug effects on bloodpressure, heart rate, diastolic threshold and ECG intervals are assessedat the median dose for termination of AF. Two tailed tests are used anda p<0.05 is taken to indicate statistical significance.

TABLE 2 EXPERIMENTAL GROUPS AND DOSES OF DRUGS Dose Mean dose Mediandose range Effective doses required for required for tested forterminating termination of termination of Drug (μmol/kg) AF (μmol/kg) AF(μmol/kg) AF (μmol/kg) Flecainide 1.25-10 4-2.5; 1-10 4 ± 2 2.5

A single drug was administered to each dog over the dose range specifieduntil AF was terminated. The number of dogs in which AF was terminatedat each dose is shown (number of dogs-dose, in μmol/Kg). The mean±SEM aswell as the median dose required to terminate AF is shown. Each dogreceived only one drug.

Compounds of the present invention may be evaluated by this method. Theeffectiveness of flecainide as a control in the present study wascomparable to that previously reported.

Canine Sterile Pericarditis Model

This model has been used to characterize the mechanisms of AF and atrialflutter (AFL). Waldo and colleagues have found that AF depends onreentry and that the site of termination is usually an area of slowedconduction. This canine model is prepared by dusting the exposed atriawith talcum powder followed by “burst” pacing the atria over a period ofdays after recovery. AF is inducible two days after surgery, however, bythe fourth day after surgical preparation; sustainable atrial flutter isthe predominant inducible rhythm. The inducibility of AF at day 2 issomewhat variable, such that only 50% of dogs may have sustained AF(generally <60 minutes) for a requisite of 30 minutes. However, thesustainable atrial flutter that evolves by the fourth day is induciblein most preparations. Atrial flutter is more readily “mapped” forpurposes of determining drug mechanisms. Inducibility of AF subsidesafter the fourth day post-surgery, similar to the AF that often developsfollowing cardiac surgery that the sterile pericarditis model mimics.There may be an inflammatory component involved in the etiology ofpost-surgery AF that would provide a degree of selectivity to anischaemia or acid selective drug. Similarly, while coronary arterybypass graft (CABG) surgery is performed to alleviate ventricularischaemia, such patients may also be at risk for mild, atrial ischaemiadue to coronary artery disease (CAD). While atrial infarcts are rare,there has been an association between AV nodal artery stenosis and riskfor AF following CABG surgery. Surgical disruption of the autonomicinnervation of the atria may also play a role in AF following CABG.

Methods

Studies are carried out in a canine model of sterile percarditis todetermine the potency and efficacy of compounds of the present inventionin terminating atrial fibrillation/flutter. Atrial flutter orfibrillation was induced 2 to 4 days after creation of sterilepericarditis in adult mongrel dogs weighing 19 kg to 25 kg. In allinstances, the atrial fibrillation or flutter lasted longer than 10minutes.

Creation of the Sterile Pericarditis Atrial Fibrillation/Flutter Model

The canine sterile pericarditis model is created as previouslydescribed. At the time of surgery, a pair of stainless steel wireelectrodes coated with FEP polymer except for the tip (O Flexon, Davisand Geck) are sutured on the right atrial appendage, Bachman's bundleand the posteroinferior left atrium close to the proximal portion of thecoronary sinus. The distance between each electrode of each pair isapproximately 5 mm. These wire electrodes are brought out through thechest wall and exteriorized posteriorly in the interscapular region forsubsequent use. At the completion of surgery, the dogs are givenantibiotics and analgesics and then are allowed to recover.Postoperative care included administration of antibiotics andanalgesics.

In all dogs, beginning on postoperative day 2, induction of stableatrial fibrillation/flutter is attempted in the conscious, non-sedatedstate to confirm the inducibility and the stability of atrialfibrillation/flutter and to test the efficacy of the drugs. Atrialpacing is performed through the electrodes sutured during the initialsurgery. On postoperative day 4, when stable atrial flutter is induced,the open-chest study is performed.

For the open-chest study, each dog is anesthetized with pentobarbital(30 mg/kg IV) and mechanically ventilated with 100% oxygen by use of aBoyle model 50 anesthesia machine (Harris-Lake, Inc.). The bodytemperature of each dog is kept within the normal physiological rangethroughout the study with a heating pad. With the dog anesthetized, butbefore the chest is opened, radiofrequency ablation of the His bundle isperformed to create complete atrioventricular (AV) block by standardelectrode catheter techniques. This is done to minimize thesuperimposition of atrial and ventricular complexes during subsequentrecordings of unipolar atrial electrograms after induction of atrialflutter. After complete AV block is created, an effective ventricularrate is maintained by pacing of the ventricles at a rate of 60 to 80beats per minute with a Medtronic 5375 Pulse Generator (Medtronic Inc.)to deliver stimuli via the electrodes sutured to the right ventricleduring the initial surgery.

Determination of Stimulus Thresholds and Refractory Periods DuringPacing

For the induction of AF/AFL, one of two previously described methods isused: (1) introduction of one or two premature atrial beats after atrain of 8 paced atrial beats at a cycle length of 400 ms, 300 ms, 200ms, or 150 ms, or (2) rapid atrial Pacing for Periods of 1 to 10 secondsat rates incrementally faster by 10 to 50 beats per minute than thespontaneous sinus rate until atrial flutter is induced or there is aloss of 1:1 atrial capture. Atrial pacing is performed from either theright atrial appendage electrodes or the posteroinferior left atrialelectrodes. All pacing is performed using stimuli of twice threshold foreach basic drive train with a modified Medtronic 5325 programmable,battery-powered stimulator with a pulse width of 1.8 ms.

After the induction of stable atrial fibrillation/flutter (lastinglonger than 10 minutes), the atrial fibrillation/flutter cycle length ismeasured and the initial mapping and analysis are performed to determinethe location of the atrial fibrillation/flutter reentrant circuit.Atrial flutter is defined as a rapid atrial rhythm (rate, >240 beats perminute) characterized by a constant beat-to-beat cycle length, polarity,morphology, and amplitude of the recorded bipolar electrograms.

Drug Efficacy Testing Protocol

1. Effective refractory periods (ERPs) are measured from three sites:right atrial appendage (RAA), posterior left atrium (PLA), and Bachman'sBundle (BB), at two basic cycle lengths 200 and 400 ms.

2. Pace induce A-Fib or AFL. This is attempted for one hour. If noarrhythmia is induced, no further study is done on that day.

3. If induced, AF must have been sustained for 10 minutes. Then awaiting period is allowed for spontaneous termination or 20 minutes,whichever came first.

4. AF is then reinduced and 5 minutes is allowed before starting druginfusion.

5. Drug is then infused in a bolus over 5 minutes.

6. If AF terminated with the first dose then a blood sample is taken andERP measurements are repeated.

7. Five minutes is allowed for the drug to terminate. If there is notermination then the second dose is given over 5 minutes.

8. After termination and ERPs are measured, a second attempt to reinduceAF is tried for a period of ten minutes.

9. If reinduced and sustained for 10 minutes, a blood sample is takenand the study repeated from #3 above.

10. If no reinduction, then the study is over.

Compounds of the present invention may be evaluated by this method.

Assessment of Pain Blockage

CD-1 mice (20-30 g) are restrained in an appropriate holder. Atourniquet is placed at the base of the tail and a solution of the testcompound (50 μl, 5 mg/ml) is injected into the lateral tail vein. Thetourniquet is removed 10 min after the injection. Suitable dilutions ofcompound solution are used to obtain an ED₅₀ for pain blockade atvarious times after injection. Pain responses are assessed by pin prickat regular intervals up to 4 hours post injection and the duration ofpain blockage is recorded for three animals for each test compoundsolution. Compounds of the present invention may be evaluated accordingto the method described.

In Vitro Assessment of Inhibition Activity of Ion Channel ModulatingCompounds on Different Cardiac Ionic Currents

Cell Culture:

The relevant cloned ion channels (e.g., cardiac hH1Na, Kv1.4, Kv1.5,Kv4.2, Kv2.1, HERG etc.) are studied by transient transfection into HEKcells using the mammalian expression vector pCDNA3. Transfections foreach channel type are carried out separately to allow individual studyof the ion channel of interest. Cells expressing channel protein aredetected by cotransfecting cells with the vector pHook-1 (Invitrogen,San Diego, Calif., USA). This plasmid encoded the production of anantibody to the hapten phOX, which when expressed is displayed on thecell surface. Equal concentrations of individual channel and pHook DNAare incubated with 10× concentration of lipofectAce in Modified Eagle'sMedium (MEM, Canadian Life Technologies) and incubated with parent HEKcells plated on 25 mm culture dishes. After 3-4 hours the solution isreplaced with a standard culture medium plus 20% fetal bovine serum and1% antimycotic. Transfected cells are maintained at 37° C. in an air/5%CO² incubator in 25 mm Petri dishes plated on glass coverslips for 24-48hours to allow channel expression to occur. 20 min prior to experiments,cells are treated with beads coated with phOX. After 15 min, excessbeads are ished off with cell culture medium and cells which had beadsstuck to them are used for electrophysiological tests.

Solutions:

For whole-cell recording the control pipette filling solution contained(in mM): KCl, 130; EGTA, 5; MgCl2, 1; HEPES, 10; Na2ATP, 4; GTP, 0.1;and is adjusted to pH 7.2 with KOH. The control bath solution contained.(in mM): NaCl, 135; KCl, 5; sodium acetate, 2.8; MgCl2, 1; HEPES, 10;CaCl2, 1; and is adjusted to pH 7.4 with NaOH. The test ion channelmodulating compound is dissolved to 10 mM stock solutions in water andused at concentrations between 0.5 and 100 μM.

Electrophysiological Procedures:

Coverslips containing cells are removed from the incubator beforeexperiments and placed in a superfusion chamber (volume 250 μl)containing the control bath solution at 22 C to 23 C. All recordings aremade via the variations of the patch-clamp technique, using an Axopatch200A amplifier (Axon Instruments, CA). Patch electrodes are pulled fromthin-walled borosilicate glass (World Precision Instruments; FL) on ahorizontal micropipette puller, fire-polished, and filled withappropriate solutions. Electrodes had resistances of 1.0-2.5 μohm whenfilled with control filling solution. Analog capacity compensation isused in all whole cell measurements. In some experiments, leaksubtraction is applied to data. Membrane potentials have not beencorrected for any junctional potentials that arose between the pipetteand bath solution. Data are filtered at 5 to 10 kHz before digitizationand stored on a microcomputer for later analysis using the pClamp6software (Axon Instruments, Foster City, Calif.). Due to the high levelof expression of channel cDNA's in HEK cells, there is no need forsignal averaging. The average cell capacitance is quite small, and theabsence of ionic current at negative membrane potentials allowedfaithful leak subtraction of data.

Data Analysis:

The concentration-response curves for changes in peak and steady-statecurrent produced by the test compound are computer-fitted to the Hillequation:f=1−1/[1+(IC ₅₀ [D])^(n)]  [1]where f is the fractional current (f=Idrug/Icontrol) at drugconcentration [D]; IC₅₀ is the concentration producing half-maximalinhibition and n is the Hill coefficient.

Compounds of the present invention may be evaluated by this method. Theresults show that compounds of the present invention tested havedifferent degree of effectiveness in blocking various ion channels.Block is determined from the decrease in peak hH1 Na⁺ current, or insteady-state Kv1.5 and integrated Kv4.2 current in the presence of drug.To record Na⁺ current, cells are depolarized from the holding potentialof −100 mV to a voltage of −30 mV for 10 ms to fully open and inactivatethe channel. To record Kv1.5 and Kv4.2 current, cells are depolarizedfrom the holding potential of −80 mV to a voltage of +60 mV for 200 msto fully open the channel. Currents are recorded in the steady-state ata range of drug concentrations during stimulation every 4 s. Reductionin peak current (Na⁺ channel), steady-state current (Kv1.5 channel) orintegrated current (Kv4.2) at the test potential of −30 mV (Na⁺ channel)or +60 mV (Kv1.5 and Kv4.2 channel) is normalized to control current,then plotted against the concentration of test compound. Data areaveraged from 4-6 cells. Solid lines are fit to the data using a Hillequation. The IC₅₀ values for some of the compounds of the presentinvention on various ion channels studied are summarized in thefollowing table (Table 3):

TABLE 3 Compound # Kv1.5 hERG Kv4.2 H1Na Kv2.1 1 3.2 7 50 18.6 2 6 2036.4 3 5 35 30.3 6 6 20 25.4 7 6 35 37.2

The activity of other compounds of the present invention to modulatevarious ionic currents of interest may be similarly studied.

Assessment of Proarrhythmia (Torsade de Pointes) Risk of Ion ChannelModulating Compounds in Primates

Methods

General Surgical Preparation:

All studies are carried out in male Macaca fascicularis weighing between4 and 5.5 kg. Animals are fasted over night and pre-medicated withketamine (10 mg/kg im). Both saphenous veins are cannulated and a salinedrip instituted to keep the lines patent. Halothane anaesthesia (1.5% inoxygen) is administered via a face mask. Lidocaine spray (10% spray) isused to facilitate intubation. After achieving a sufficient depth ofanaesthesia, animals are intubated with a 4 or 5 French endotrachealtube. After intubation halothane is administered via the endotrachealtube and the concentration is reduced to 0.75-1%. Artificial respirationis not used and all animals continue to breathe spontaneously throughoutthe experiment. Blood gas concentrations and blood pH are measured usinga blood gas analyser (AVO OPTI I). The femoral artery is cannulated torecord blood pressure.

Blood pressure and a modified lead II ECG are recorded using a MACLAB 4Srecording system paired with a Macintosh PowerBook (2400c/180). Asampling rate of 1 kHz is used for both signals and all data is archivedto a Jazz disc for subsequent analysis.

Vagal Nerve Stimulation:

Either of the vagi is isolated by blunt dissection and a pair ofelectrodes inserted into the nerve trunk. The proximal end of the nerveis crushed using a vascular clamp and the nerve is stimulated usingsquare wave pulses at a frequency of 20 Hz with a 1 ms pulse widthdelivered from the MACLAB stimulator. The voltage (range 2-10V) isadjusted to give the desired bradycardic response. The targetbradycardic response is a reduction in heart rate by half. In caseswhere a sufficient bradycardic response could not be obtained, 10 μg/kgneostigmine iv is administered. This dose of neostigmine is also givenafter administration of the test drug in cases where the test drug hasvagolytic actions.

Test Compounds:

A near maximum tolerated bolus dose of the test compound, infused (iv)over 1 minute, is used to assess the risk of torsade de pointer causedby each test compound. The actual doses vary slightly depending on theanimals' weight. Clofilium, 30 μmol/kg, is used as a positive comparison(control) for these studies. The expectation is that a high dose of drugwould result in a high incidence of arrhythmias. The test compounds aredissolved in saline immediately before administration.

Experimental Protocol:

Each animal receives a single dose of a given drug iv. Before startingthe experiment, two 30 second episodes of vagal nerve stimulation arerecorded. A five minute rest period is allowed between episodes andbefore starting the experiment. The test solution is administered as aniv bolus at a rate of 5 ml/minute for 1 minute using an infusion pump(total volume 5 ml). ECG and blood pressure responses are monitoredcontinuously for 60 minutes and the occurrence of arrhythmias is noted.The vagal nerve is stimulated for 30 seconds at the following timesafter injection of the drug: 30 seconds, 2, 5, 10, 15, 20, 25, 30 and 60minutes.

Blood samples (1 ml total volume) are taken from each treated animal atthe following times after drug administration: 30 seconds, 5, 10, 20, 30and 60 minutes as well as 3, 6, 24 and 48 hours. Blood samples taken upto 60 minutes after drug administration are arterial while those takenafter this time are venous. Samples are centrifuged, the plasma decantedand frozen. Samples are kept frozen before analysis of plasmaconcentration of the drug and potassium.

Statistics:

The effect of drugs on blood pressure, heart rate and ECG intervals aredescribed as the mean±SEM for a group size of “n.”

Compounds of the present invention may be evaluated by this method.

Determination of CNS Toxicity

In order to assess the activity of ion channel compounds in vivo it isimportant to know the maximum tolerated dose. Here CNS toxicity wasassessed by investigating the minimum dose of a compound which inducespartial or complete convulsions in conscious rats. The procedure avoidsusing lethality as an end point as well as avoiding unnecessarysuffering as the experiment is terminated if this appears likely. Shouldthe drug precipitate a life threatening condition (e.g., severehypotension or cardiac arrhythmias) the animals are sacrificed via anoverdose of pentobarbital.

Rats weighing 200-250 g were anaesthetized with pentobarbital anestheticand subjected to preparative surgery. The femoral artery was cannulatedfor measurement of blood pressure and withdrawal of blood samples. Thefemoral vein was cannulated for injection of drugs. ECG leads wereinserted into the subcutaneous muscle layer in the region of the heartand in the region near the base of the neck and shoulder. All cannulaeand ECG leads were exteriorized in the mid scalpular region. Toalleviate post-operative pain narcotics and local anesthetics were used.Animals were returned to a recovery cage for at least 24 hours beforecommencing the experiment. Infusion of the compound was then commencedvia the femoral vein cannula. The initial rate of infusion was set at2.0 micromole/kg/min at a rate of 1 ml/hr. The infusion rate was doubledevery minute until partial or complete convulsions were observed. Themaximum infusion rate used was 64 micromole/kg/min. Rates werecontinuously monitored and end time an infusion rate noted.

Table 4, column 4 describes the results of test for the compoundsdescribed therein as values of a given infusion rate inmicromole/kg/min. (convulsion dose) which is the minimum infusion rateat which partial or complete convulsions are observed. Table 4, column 5gives the results of the test for the described compounds as values ofthe cumulative convulsion dose which is the total amount of drug infusedat the point that partial or complete convulsions are first observed.

Similarly, Table 5, column 4 describes the results of test for thecomparative example compounds described therein as values of a giveninfusion rate in micromole/kg/min. (convulsion dose) which is theminimum infusion rate at which partial or complete convulsions areobserved. Table 5, column 5 gives the results of the test for thedescribed comparative example compounds as values of the cumulativeconvulsion dose which is the total amount of drug infused at the pointthat partial or complete convulsions are first observed.

Determination of Therapeutic Index

The therapeutic index for the compounds 1 to 7 (Table 4) according tothe invention and comparative example compounds 8 to 49 (Table 5) wascalculated using formula the following:Cumulative convulsion dose/(20×ED₅₀AA)

Tables 4 and 5, column 7, give the calculated value for the therapeuticindex of the compounds described therein.

TABLE 4 Convul- cum sion conv ED₅₀A dose dose A Thera- Cpd (umol/kg/(umol/ (umol/ peutic No. Structure Chemical name g/min) kg) kg/min)index* 1

(1R,2R)-2-[(3R)- Hydroxy- pyrrolidinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 507 1.4 18.1 2

(1S,2S)-2-[(3R)- Hydroxy- pyrrolidinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 500.67 1.2 20.9 3

(1R,2R)/(1S,2S)-2- [(3R)/(3S)- Hydroxy- pyrroldinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 502 1.3 19.3 4

(1R,2R)/(1S,2S)-2- [(3R)- Hydroxy- pyrrolidinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 502 0.8 31.4 5

(1R,2R)/(1S,2S)-2- [(3S)-Hydroxy- pyrrolidinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 438 0.7 31.3 6

(1R,2R)-2-[(3S)- Hydroxy- pyrrolidinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 472.24 1.6 14.8 7

(1S,2S)-2-[(3S)- Hydroxy- pyrrolidinyl]-1-(3,4- dimethoxy-phenethoxy)-cyclohexane monohydrochloride 64 451.67 0.9 25.1

As shown by Table 4 above, the compounds according to the presentinvention, having the specified dimethoxyphenylethoxy group at position1 of the cyclohexyl ring and hydroxypyrrolidine group at position 2 ofthe cyclohexyl ring, exhibit low CNS toxicity together with highantiarrhythmic activity. The experimental results recited above clearlyindicate the compounds of the present invention for the effectivetreatment of arrhythmia. Whereas comparative example compounds 8 to 22containing only the specified dimethoxyphenylethoxy group at position 1of the cyclohexyl ring and comparative example compounds 23 to 29 havingonly the specified hydroxypyrrolidine group at position 2 of thecyclohexyl ring, exhibit both higher CNS toxicity together with lowerantiarrhythmic activity when compared with the compounds of the presentinvention (compounds 1 to 7 shown in Table 4). Accordingly, thetherapeutic indexes of the compounds of the present invention are muchbetter. Additional comparative example compounds 30 to 48 correspond tothe examples described in WO 99/50225. The test results with thesecompounds again showed higher CNS toxicity together with lowerantiarrhythmic activity than the compounds of the present invention.

TABLE 5 Convul- sion cum ED50 Compa- dose conv AA rative (umol/ dose(umol Thera- Example Chemical kg/ (umol/ kg/ peutic Cpd No. Structurename min) kg) min) index 8

4-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl) ethoxy]cyclo-hexyl}mor- pholine hydrochloride 16 113 1.5 3.8 9

7-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)- ethoxy]cyclo-hexyl}- 1,4-dioxa-7- azaspiro[4.4] nonane hydrochloride 16 91.33 1.6 2.910

1-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)- ethoxy]cyclo-hexyl}- pyrrolidine hydrochloride 21.33 118 1.33 4.4 11

(3S)-3- benzyloxy- 1-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)-ethoxy]cyclo- hexyl}- pyrrolidine hydrochloride 8 38.13 0.5 3.8 12

(3R)-3- benzyloxy- 1-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)-ethoxy] cyclohexyl}- pyrrolidine hydrochloride 8 51.1 1 2.6 13

(3S)-1- {(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)- ethoxy]cyclohexyl}- pyrrolidin- 3-yl acetate hydrochloride 8 51.9 1.3 2 14

(3R)/(3S)- 1-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)- ethoxy]cyclohexyl}- 3-fluoro- pyrrolidine hydrochloride 10.67 63.33 1.4 2.3 15

{(2R)-1- {(1R,2R)/ (1S,2S)-2-[2- (3,4- dimethoxy- phenyl)- ethoxy]cyclohexyl}- pyrrolidin- 2-yl} methanol hydrochloride 16 142.33 0.8 8.916

1-{(1R,2R)/ (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)- ethoxy]cychlohexyl}- 2,5-dihydro- 1H-pyrrole hydrochloride 8 44.4 2.4 0.9 17

(3R)-1- {(1R,2R)- 2-[2-(3,4- dimethoxy- phenyl)- ethoxy] cyclohexyl}-pyrrolidin- 3-yl acetate hydrochloride 13.33 74.3 2.1 1.8 18

1-{(1R,2R) (1S,2S)-2- [2-(3,4- dimethoxy- phenyl)- ethoxy] cyclohexyl}-pyrrolidin- 3-one hydrochloride 32 235 4.5 2.6 19

4-{(1R,2R)/ (1S,2S)-2- [3-(3,4- dimethoxy- phenyl)- propoxy] cyclohexyl}morpholine hydrochloride 16 109 1.5 3.6 20

4-{(1R,2R)/ (1S,2S)-2- [4-(3,4- dimethoxy- phenyl)- butoxy] cyclohexyl}morpholine hydrochloride 10.7 66.8 1.5 2.2 21

(3R)-1- {(1R,2R)/ (1S,2S)-2- [3-(3-chloro- 4,5- dimethoxy- phenyl)-propoxy] cyclohexyl} pyrrolidin- 3-ol hydrochloride 13.33 90.9 0.6 7.622

1-[(3,4- dimethoxy- phenyl) acetyl]-4- {(1R,2R)/ (1S,2S)-2- [2-(3,4-dimethoxy- phenyl)- ethoxy] cychlohexyl}- piperazine hydrochloride 21.33133 0.6 11.1 23

(3R)/(3S)- 1-{(1R,2R)/ (1S,2S)-2- [2-(2,6- dichlorophe- nyl)-ethoxy]cyclohexyl}- pyrrolidin- 3-ol hydrochloride 8 65 0.6 5.4 24

(3R)/(3S)- 1-{(1R,2R)/ (1S,2S)-2- [2-(2- bromophe nyl)-ethoxy]cyclohexyl}- pyrrolidin- 3-ol hydrochloride 13 67 0.4 8.4 25

(3R)/(3S)- 1-{(1R,2S)/ (1S,2R)-2- [2-(1- naphthyl) ethoxy]- cyclohexyl}-pyrrolidin- 3-ol hydrochloride 16 70 0.4 8.8 26

(3R)/(3S)- 1-{(1R,2R)/ (1S,2S)-2-[2- (1-naphthyl) ethoxy]- cyclohexyl}-pyrrolidin- 3-ol hydrochloride 8 67.33 0.78 4.3 27

(3R)-1- {(1R,2R)/ (1S,2S)-2- [2-(2- Trifluoro methyl- phenyl) ethoxy]-cyclohexyl}- pyrrolidin- 3-ol hydrochloride 16 101.93 0.7 7.3 28

(3R)/(3S)- 1-{(1R,2R)/ (1S,2S)-2- [2-(1H-indol- 1-yl)ethoxy] cyclohexyl}pyrrolidin- 3-ol hydrochloride 16 113 0.6 9.4 29

(3R)-1- {(1R,2R)/ (1S,2S)-2- [2-(1- benzofuran- 2-yl)ethoxy]-cyclohexyl}- pyrrolidin- 3-ol hydrochloride 10.67 65.67 1 3.3 30

(1R,2R)/(1S, 2S)-[2-(4- morpholinyl)- 1-(2- naphthene thoxy)]-cyclohexane 13.3 85 0.8 5.3 31

(1R,2R)/(1S, 2S)-[2-(4- morpholinyl)- 1-(1- naphthene thoxy)]-cyclohexane 16 93 1 4.7 32

(1R,2R)/1S, 2S)-[2-(4- morpholinyl)- 1-(4-bromo- phenethoxy)]-cyclohexane 12 91 2.1 2.2 33

(1R,2R)/(1S, 2S)-[2-(4- morpholinyl)- 1-[2-(2- naphthoxy) ethoxy]]-cyclohexane 8 61.63 2 1.5 34

(1R,2R)/(1S, 2S)-[2-(4- morpholinyl)- 1-[2-(4- bromo- phenoxy)- ethoxy]]cyclohexane 10.7 83 3 1.4 35

(1R,2R)/(1S, 2S)-[2-(4- morpholin yl)-1-(3,4- dimethoxy- phenethoxy)]-cyclohexane 16 113 4 1.4 36

(1R,2R)/(1S, 2S)-[2-(4- morpholinyl)- 1-(2-(benzo [b]thiophen- 3-yl)]cyclohexane 8 65 1 3.3 37

(1R,2R)/(1S, 2S)-[2-(4- morpholinyl)- 1-(2-(benzo[b] thiophen-4-yl)]cyclo- hexane 8 54 1 2.7 38

(1R,2R)/(1S, 2S)-[2- (4- morpholin yl)-1-(3- bromo- phenethoxy)]-cyclohexane 16 131 2 3.3 39

(1R,2R)/(1S, 2S)-[2- (4- morpholin yl)-1-(2- bromo- phenethoxy)]-cyclohexane 16 125 1 6.3 40

(1R,2R)/(1S, 2S)-2-(4- morpholinyl)- 1-(3,4- dichloro- phenethoxy)cyclohexane 16 118 1.5 3.9 41

(1R,2R)/(1S, 2S)-2-(3- ketopyrroli- dinyl)-1-(2,6- dichloro- phenethoxy)cyclohexane monohydro- chloride 32 190 1.1 8.6 42

(1R,2S)/(1S, 2R)-2-(4- morpholinyl)- 1-[(2-trifluo- romethyl)-phenethoxy]- cyclohexane monohydro- chloride 16 102 1.4 3.6 43

(1R,2R)/(1S, 2S)-2-(3- acetoxy pyrrolidinyl)- 1-(1- naphthenethoxy)cyclo- hexane monohydro- chloride 8 65 1.4 2.3 44

(1R,2R)/(1S, 2S)-2-(4- morpholinyl)- 1-[(2,6- dichlorophe- nyl)methoxy]cyclohexane monohydro- chloride 16 97 1.8 2.7 45

(1R,2R)/(1S, 2S)-2-(3- ketopyrroli- dinyl)-1-[(2,6- dichlorophe-nyl)methoxy] cyclohexane monohydro- chloride 32 214 2.1 5.1 46

(1R,2R)/(1S, 2S)-2-(3- hydroxypyr- rolidinyl)- 1-(2,6- dichlorophe-nethoxy) cyclohexane monohydro- chloride 8 65 0.6 5.4 47

(1R,2R)/(1S, 2S)-2-(3- ketopyrroli- dinyl)-1-(2,2- diphenyleth-oxy)cyclo- hexane monohydro- chloride 21 155 2.5 3.1 48

(1R,2R)/(1S, 2S)-2-(3- thiazolidinyl)- 1-(2,6- dichlorophen- ethoxy)cyclohexane monohydro- chloride 43 331 6.5 2.5

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually incorporated by reference.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited by the specific embodiments and examples contained in thispatent.

1. A method of stereoselectively making an aminocyclohexyl ethercomprising: reacting a compound of formula (55),

or a compound of formula (74),

with a compound of formula (56),

to form a compound of formula (57),

or a compound of formula (75),

respectively, wherein R₁ and R₂, when taken together with the nitrogenatom to which they are directly attached in formula (57) or (75), form aring denoted by formula (II):

wherein the method further comprises making the compound of formula (74)or formula (55) by activating a compound of formula (73),

or a compound of formula (94),

with a hydroxy activating reagent to form the compound of formula (74)or the compound of formula (55), respectively; wherein the methodfurther comprises making a compound of formula (73) by hydrogenating andhydrogenolyzing a compound of formula (72),

to form the compound of formula (73); wherein the method furthercomprises making a compound of formula (72) by alkylating a compound offormula (51),

with a compound of formula (54),

to form the compound of formula (72); wherein X is a halide; wherein O-Jis a leaving group; wherein R₃, R₄ and R₅ are independently selectedfrom hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄and R₅ cannot all be hydrogen; and wherein O-Q is a leaving group thatreacts with —OH in the compound of formula (51) to form the compound offormula (72), such that the stereochemical configuration of the compoundof formula (51) is retained in the compound of formula (72).
 2. A methodof making a compound of compound of formula (93):

wherein the method comprises: alkylating a compound of formula (92),

with a compound of formula (54),

to form the compound of formula (93); wherein the method furthercomprises making a compound of formula (92) by hydrogenating andhydrogenolyzing a compound of formula (91),

to form the compound of formula (92); wherein Pro is a protecting group;wherein X is a halide; wherein R₃R₄ and R₅ are independently selectedfrom hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄and R₅ cannot all be hydrogen; and wherein O-Q is a leaving group thatreacts with —OH in the compound of formula (92) to form the compound offormula (93), such that the stereochemical configuration of the compoundof formula (92) is retained in the compound of formula (93).
 3. A methodof stereoselectively making an aminocyclohexyl ether comprising:reacting a compound of formula (55),

or a compound of formula (74),

with a compound of formula (56),

to form a compound of formula (57),

or a compound of formula (75),

respectively, wherein R₁ and R₂, when taken together with the nitrogenatom to which they are directly attached in formula (57) or (75), form aring denoted by formula (II):

and wherein the method further comprises making a compound of formula(55) or formula (74) by alkylating a compound of formula (53),

or a compound of formula (84),

with a compound of formula (54),

to form the compound of formula (55) or the compound of formula (74);respectively; and optionally protecting the compound of formula (53) orthe compound of formula (84), before said alkylating step; wherein O-Qis a leaving group that reacts with —OH in formula (53) or formula (84)to form the compound of formula (55) or the compound of formula (74),such that the stereochemical configuration of the compound of formula(53) or the compound of formula (84) is retained in the compound offormula (55) or the compound of formula (74), respectively; wherein themethod further comprises making the compound of formula (53) byhydrogenating and hydrogenolyzing a compound of formula (52),

to form the compound of formula (53); wherein X is a halide; wherein O-Jis a leaving group; and wherein R₃R₄ and R₅ are independently selectedfrom hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄and R₅ cannot all be hydrogen.
 4. The method of claim 3, wherein themethod further comprises making a compound of formula (52):

wherein the method comprises: activating a compound of formula (51),

with a hydroxy activating reagent to form the compound of formula (52);wherein X is a halide; and wherein O-J is a leaving group.
 5. A methodof making an aminocyclohexyl ether comprising: reacting a compound offormula (55),

or a compound of formula (74),

with a compound of formula (56),

to form a compound of formula (57),

or a compound of formula (75),

respectively, wherein R₁ and R₂, when taken together with the nitrogenatom to which they are directly attached in formula (57) or (75), form aring denoted by formula (II):

and wherein the method further comprises stereoselectively making theaminocyclohexyl ether of formula (57) by (a) hydrogenating andhydrogenolyzing a compound of formula (91),

to form a compound of formula (92),

wherein Pro is a protecting group and X is a halide; (b) alkylating thecompound of formula (92) with a compound of formula (54),

wherein R₃, R₄ and R₅ are as defined above and O-Q is a leaving groupthat reacts with the hydroxy group in formula (92) to form a compound offormula (93),

such that the stereochemical configuration of the compound of formula(92) is retained in the compound of formula (93); (c) deprotecting thecompound of formula (93) to form a compound of formula (94),

(d) activating the compound of formula (94) to form a compound offormula (55),

wherein O-J is a leaving group; and (e) reacting the compound of formula(55) with a compound of formula (56),

wherein R₁ and R₂ are as defined above, to form the aminocyclohexylether of formula (57); wherein R₃, R₄ and R₅ are independently selectedfrom hydrogen, hydroxy and C₁-C₆alkoxy, with the proviso that R₃, R₄ andR₅ cannot all be hydrogen; and wherein O-J is a leaving group.